Triazole antifungal agent

ABSTRACT

A triazole compound having the formula:                    
     wherein Ar 1  represents a phenyl group which may be substituted; Ar 2  represents a phenyl group which may be substituted; R 0  represents a hydrogen atom or a lower alkyl; R 1  represents a lower alkyl; R 2  to R 5  each represnet a hydrogen atom or an unsubstituted or halo substituted alkyl; n represnets 0 to 2; p represents 0 or 1; q, r and s each represent 0 to 2; A represents a 4- to 7-membered carbon ring or a 4- to 7-membered heterocyclic, not including 1,3-dioxan-5-yl. The compound of the present invention exhibits an excellent antifungal activity.

This application is a divisional application of application Ser. No.08/944,304, filed Oct. 6, 1997, (U.S. Pat. No. 5,977,152) which is acontinuation-in-part of application of International applicationPCT/JP96/00932 filed Apr. 5, 1996, which is hereby incorporated in itsentirety.

The present invention relates to a 1,2,4-triazole compound representedby the formula (I) which is particularly effective for mycotic diseaseof a human being and an animal.

BACKGROUND OF THE INVENTION

In the Japanese Unexamined Patent Publication (KOKAI) No. Sho 61-85369,it is described that an analogous compound of the compound of thepresent invention, in which the following moiety (which corresponds tothe right hand moiety of formula (I) which starts with —A—):

—A—(CO)_(p)—(R²C═CR³)_(q)—(C≡C)_(r)—(R⁴C═CR⁵)_(s)—Ar²

is bonded to an alkyl, a cycloalkylalkyl group or a cycloalkyl group,has antifungal activities.

However, the present inventors made intensive studies in order to find amore excellent antifungal agent and found that the compound of thepresent invention is an excellent antifungal agent to accomplish thepresent invention.

SUMMARY OF THE INVENTION

The present invention relates to a compound having the formula

wherein

Ar¹ represents a phenyl group or a phenyl group having 1 to 3substituent(s), (the substituent(s) represent(s) a halogen atom or atrifluouromethyl group);

Ar² represents a phenyl group, a 5- or 6-membered aromatic heterocyclicgroup (the aromatic heterocyclic group has at least one nitrogen, oxygenor sulfur atom) or a phenyl group or a 5- or 6-membered aromaticheterocyclic group having 1 to 3 substituents [the substituent(s)represents(s) a lower alkyl group, a lower alkoxy group, a halogen atom,a lower alkyl group substituted with a halogen atom or halogen atoms, alower alkoxy gorup substituted with a halogen atom or halogen atoms, anitro group, a cyano group, a —S(O)_(m)R⁶ group (R⁶ represnets a loweralkyl group which may be substituted with a halogen atom or halogenatoms and m represents 0, 1 or 2 or a —NHCOR⁷ group (R⁷ represnts alower alkyl group) and the aromatic heterocyclic group has at least onenitrogen, oxygen or sulfur atom];

R⁰ represnets a hydrogen atom or a lower alkyl group;

R¹ represents a lower alkyl group;

R², R³, R⁴ and R⁵ may be the same or different and respresent a hydrogenatom, a lower alkyl group or a lower alkyl group substituted with ahalogen atom or halogen atoms and, where q and/or s represent 2, each ofR², R³, R⁴ and R⁵ represents independently a group which is the same ordifferent from the other R², R³, R⁴ and R⁵ respectively;

n represents 0, 1, or 2 ;

p represents 0 or 1;

q, r and s represent 0, 1 or 2; and

A represents a 4- to 7-membered aliphatic carbocyclic group comprising 4to 7 carbon atoms or a 4- to 7-membered aliphatic heterocyclic grouphaving at least one nitrogen, oxygen or sulfur atom,

or a pharmacologically acceptable salt thereof.

The above-mentioned halogen atom is, for example, a flourine, chlorineor bromine atom, preferably a flourine or chlorine atom.

The lower alkyl group is, for example, a methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl or tert-butyl group, preferably amethyl, ethyl, propyl or isopropyl group.

The lower alkoxy group is, for example, a methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy group,preferably a methoxy, ethoxy, propoxy or isopropoxy group.

The 5- or 6-membered aromatic heterocyclic group of Ar² is, for example,a furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl,pyridyl, pyrimidyl or pyrazyl group, preferably a furyl, thienyl,pyrrolyl or pyridyl group.

The 4- to 7-membered aliphatic carbocyclic group comprising 4 to 7carbon atoms of A is, for example, a cyclobutane, cyclopentane,cyclohexane or cyclobutane ring, preferably a cyclobutane, cyclopentaneor cyclohexane ring.

The 4- to 7-membered aliphatic heterocyclic group having at least onenitrogen, oxygen or sulfur atom of A is, for example, an azetidine,pyrrolidine, piperidine, homopiperidine, oxetane, tetrahydrofuran,tetrahydropyran, thietane, tetrahydrothiophene, pentamethylenesulfide,1,4,5,6-tetrahydropyrimidine, 1,3-dioxane, 1,3- dithiane, dihydroxazine,tetrahydroxazine, dihydrothiazine or tetrahydrothiazine ring, preferablyan azetidine, piperidine, 1,3-dioxane, 1,4,5,6-tetrahydropyrimidine,tetrahydroxazine or 1,3-dithiane ring.

The preferable compound having the formula (I) is the compound in which:

Ar¹ is a dichlorophenyl, difluorophenyl, chlorophenyl, fluorophenyl,(trifluoromethyl)phenyl or fluoro (trifluoromethyl)phenyl group,preferably a 2,4-dichlorophenyl, 2,4-difluorophenyl, 4- chlorophenyl,4-fluorophenyl, 4-(trifluoromethyl)phenyl or2-fluoro-4-(trifluoromethyl)phenyl group, particularly preferably a2,4-dicholorphenyl, 2,4-difluorophenyl or 4-(trifluoromethyl)phenylgroup;

Ar² is a fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl,(trifluoromethyl)phenyl, (trichloromethyl)phenyl,fluoro-(trifluoromethyl)phenyl, (difluoromethoxy)phenyl,(trifluoromethoxy)phenyl, (2,2,2-trifluoroethoxy)phenyl,(1,1,2,2-tetrafluoroethoxy)phenyl, (2,2,3,3-tetrafluoropropoxy)phenyl,fluoro-(2,2,3,3-tetrafluoropropoxy)phenyl, nitrophenyl,fluoro-nitrophenyl, cyanophenyl, chloro-cyanophenyl, (methylthio)phenyl,(methylsulfinyl)phenyl, (methylsulfonyl)phenyl,(trifluoromethylthio)phenyl, (trifluoromethylsulfinyl)phenyl,(trifluoromethylsulfonyl)phenyl, chloropyridyl,(trifluoromethyl)pyridyl, (2,2,3,3-tetrafluoropropoxy)pyridyl,(trifluoromethyl)furyl, chlorothienyl or (trifluoromethyl)thienyl group,preferably a 4-fluorophenyl, 4-chlorophenyl, 2,4-difluorophenyl,2,4-dichlorophenyl, 4-(trifluoromethyl)phenyl,4-(trifluoromethyl)phenyl, 4-(trichloromethyl)phenyl,2-flouro-4-(trifluoromethyl)phenyl, 4-(difluoromehtoxy)phenyl,3-(trifluoromethoxy)phenyl, 4-(trifluoromethoxy)phenyl,4-(2,2,2-trifluoroethoxy)phenyl, 4-(1,1,2,2-tetrafluoroethoxy)phenyl,4-(2,2,3,3-tetrafluoropropoxy)phenyl,2-fluoro-4-(2,2,3,3-tetrafluoropropoxy)phenyl, 4-nitrophenyl,2-fluoro-4-nitrophenyl, 4-cyanophenyl, 2-chloro-4-cyanophenyl,4-(methylthio)phenyl, 4-(methylsulfinyl)phenyl,4-(methylsulfonyl)phenyl, 4-(trifluoromethylthio)phenyl,4-trifluoromethylthio)phenyl, 4-(trifluouromethylsulfinyl)phenyl,4-(trifluoromethylsulfonyl)phenyl, 6-chloro-3-pyridyl,6-(trifluoromethyl)-3-pyridyl, 5-chloro-2-pyridyl,6-(2,2,3,3-tetrafluoropropoxy)-3-pyridyl, 5-(trifluoromethyl)-2-furyl,5-chloro-2-thienyl or 5-(trifluoromethyl)2-thienyl group, particularlypreferably a 4-chlorophenyl, 4-(trifluoromethylthio)phenyl,4-(trifluoromethylsulfonyl)phenyl, 4-(trifluoromethyl)phenyl,4-(trifluoromethoxy)phenyl or 4-(2,2,3,3-tetrafluoropropoxy)phenylgroup;

R⁰ is a hydrogen atom, a methyl, ehtyl or propyl group, preferably ahydrogen atom, a methyl or ethyl group, particularly preferably ahydrogen atom or a methyl gorup;

R¹ is a methyl, ehtyl or propyl group, preferably a methyl or ethylgroup, particularly preferably a methyl group;

R², R³, R⁴ and R⁵ may be the same or differnt and are a hydrogen atom, amethyl, ethyl, propyl or trifluoromethyl group, preferably a hydrogenatom, a methyl or trifluoromethyl group, particularly preferably ahydrogen atom or a trifluoromethyl group;

n is 0, 1 or 2, particularly preferably 0;

p is 0 or 1, particularly preferably 0;

q is 0, 1 or 2, particularly preferably 1;

r is 0, 1 or 2, particularly preferably 0 or 1;

s is 0, 1 or 2, particularly preferably 1;

A is a cyclobutane, cyclopentane, cyclohexane, azetidine, pyrrolidine,piperidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiopene,1,3-dioxane, 1,3-dithiane, tetrahydroxazine or tetrahydrothiazine ring,preferably a cyclobutane, cyclohexane, azatidine, piperidine,1,3-dioxane, 1,3-ditaiane, tetrahydroxazine or tetrahydrothianine ring,particularly preferably a cyclohexane, peperidine, 1,3-dioxane,1,3-dithiane ring.

The preferable compound (I) can be exemplified by the compound in whichAr¹ is a 4-chlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl or4-(trifluoromethyl)phenyl group; R⁰ is a hydrogen atom or a methylgroup; R¹ is a methyl group; and the moiety represented by the formula:

—S(O)_(n)—A—(CO)_(p)—(R²C═CR³)_(q)—(C≡C)_(r)—(R⁴C═CR⁵)_(s)—Ar²

is a group as shown in Table 1.

TABLE 1 Example —S(O)n-A-(CO)p-(R²C═CR³)q-(C≡C)r-(R⁴C═CR⁵)s-Ar² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

Preferred compounds in Table 1 include those having the substituents of4, 6, 7, 13, 16, 18, 22, 25, 32, 36, 40, 43, 44, 47, 52, 53, 61, 63, 71,76, 96, 107, 123, 127, 142, 174, 176, 177, 178, 181, 182, 183 and 186,and particularly preferable compounds may include

2-(2,4-difluorophenyl)-3-[[2-[2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol(the compound corresponding to Example 2),

2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[2-[4-(trifluoromethoxy)phenyl]vinyl]-1,3-dioxan-5-yl]thio]-2-butanol(the compound corresponding to Example 11),

2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]1,3-dioxan-5-yl]thio]-2-butanol(the compound corresponding to Example 15),

2-(2,4-difluorophenyl)-3-[[2-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol(the compound corresponding to Example 16),

2-(2,4-difluorophenyl)-3-[[2-[4-[4-(chlorophenyl) 5,5,5trifluoro-1,3-pentadien-1-yl[-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol(the compound corresponding to Example 18),

2-(2,4-difluorophenyl)-3-[[1-[4-(trifluoromethoxy)cinnamoyl]piperidin-4-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol(the compound corresponding to Example 21),

2-(2,4-difluorophenyl)-3-[[1-[4-nitrocinnamoyl]piperidin-4-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol(the compound corresponding to Example 23),

2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[1-[5-[4-(trifluoromethoxy)phenyl]-2,4-pentadienoyl]piperidin-4-yl]thio]-2-butanol(the compound corresponding to Example 24),

3-methyl-1-(1H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-3-[[2-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol(the compound corresponding to Example 31),

2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[4-(trifluoromethylthio)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol(the compound corresponding to Example 32),

3-[[2-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-2-butanol(the compound corresponding to Example 33),

1-(1H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-3-[[2-[4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol(the compound corresponding to Example 34),

2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[4-[4-(trifluoromethylsulfinyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol(the compound corresponding to Example 35),

2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]cyclohexyl]thio]-2-butanol(the compound corresponding to Example 36),

2-2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[6-[4-(trifluoromethyl)phenyl]-1,3,5-hexatrien-1-yl]-1,3-dioxan5-yl]thio]-2-butanol(the compound corresponding to Example 37),

2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol(the compound corresponding to Example 38), and

2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[2-[4-[4-(trifluoromethyl)phenyl]-1-buten-3-yn-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol(the compound corresponding to Example 39).

The triazole compound (I) of the present invention has at least twoasymmetric carbon atoms, and optical isomers and diastereomers exist. Inthe optical isomer, both antipodes can be obtained by general opticalresolution or asymmetric synthesis. Further, the diastereomers can beseparated by conventional separation methods such as fractionalrecrystallization and chromatography. The compound (I) of the presentinvention includes one of these isomers or mixtures thereof.

The triazole compound (I) of the present invention can be used as anantifungal agent as such or in the form of a pharmacologicallyacceptable salt. The pharmacologically acceptable salt of the compound(I) includes, for example, a salt of inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid, asalt of carboxylic acids such as acetic acid, fumaric acid, maleic acid,oxalic acid, malonic acid, succinic acid, citric acid and malic acid, asalt of sulfonic acids such as methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid and toluenesulfonic acid and a salt of aminoacids such as glutamic acid and aspartic acid, preferably a salt ofcarboxylic acids.

Incidentally, a hydrate of the compound (I) and a hydrate of the salt ofthe compound (I) are also included in the compound of the presentinvention.

The compound (I) and a pharmacologically acceptable salt thereof of thepresent invention exhibit excellent antifungal activities and in thecase where the compound (I) and a pharmacologically acceptable saltthereof are used as an antifungal agent, they can be administered assuch or as a mixture, for example, with a suitable pharmacologicallyacceptable excipient or diluent orally in the form of a tablet, acapsule, a granule, a powder or a syrup or parenterally in the form ofinjection preparations.

These preparations are prepared by the known method using additives suchas exicipients (for example, sugar derivatives such as lactose, sucrose,glucose, mannitol and sorbitol; starch derivatives such as corn starch,mashed potato starch, α-starch, dextrine and carboxymethyl starch;cellulose derivatives such as cyrstalline cellulose, lowhydroxypropyl-substituted cellulose, hydroxypropylmethyl cellulose,carboxymethyl cellulose, carboxymethyl cellulose calcium and internallybridged carboxymethyl cellulose sodium; gum arabic; dextran; Pullulan;silicate derivatives such as light silicic acid anhydride, sytheticaluminum silicate and magnesium meta-silicic acid aluminate; phosphatederivatives such as calcium phosphate; carbonate derivatives such ascalcium carbonate; and sulfate derivatives such as calcium sulfate),binders (for example, the above excipients; gelatin;polyvinylpyrrolidone; and Macrogol); disintegrating agents (for exmaple,the above excipients; chemically modified startch-cellulose derivativessuch as Crosscarmelose sodium, sodium carboxymx starch and bridgedpolyvinylpyrrolidone), lubricants (for example, tac; stearic acid; andmetal stearates such as calcium stearate and magnesium stearate;colloidal silica; waxes such as beeswax and spermaceti; boric acid;glycol; carboxylic acid such as fumaric acid and adipic acid; sodiumcarboxylate such as sodium benzoate; sulfates such as sodium sulfate;leucine; lauryl sulfates such as sodium laurylsulfate and magnesiumlaurylsulfate; silicic acids such as silicic acid anhydride and silicicacid hydrate; and starch derivatives in the above excipients),stabilizers (for example, p-hydroxybenzoates such as methylparaben andpropylparaben; alcohols such as chorobutanol, benxyl alcohol andphenylethyl alcohol; benzalkonium chloride; phenols such as phenol andcresol; thimerosal; acetic anhydride; and sorbic acid); corrigents (forexample, sweeteners, sour agents and perfumes conventionally used),suspending agents (for example, polysorbate 80 nad carboxymethylcellulose sodium), diluents and solvents for preparations (for example,water, ethanol and glycerin). While the dose varies depending on thecondition and age of the patient to be treated, it is desirablyadministered 1 to 6 times daily depending on the condition: in the caseof oral administration, the lower limit of 1 mg each time (preferably 5mg) and the upper limit of 2000 mg (preferably 1000 mg) for an adult;and in the case of intravenous administration, the lower limit of 0.1 mgeach time (preferably 0.5 mg) and the upper limit of 600 mg (preferably500 mg) for an adult.

Among the compounds having the formula (I) of the present invention, thecompound (Ia) in which R⁰ is a hydrogen atom and n=0 can be preparedaccording to the process shown below:

(wherein Ar¹ and R¹ have the same meanings as defined above and R₈represents the formula:

—A—(CO)_(p)—(R²C═CR³)_(q)—(C≡C)_(r)—(R⁴C═CR⁵)_(s)—Ar²

described above). More specifically, the desired compound (Ia) isprepared by reacting an epoxide compound (2) described in JapaneseUnexamined Patent Publication (KOKAI) No. Hei 2-191262 (Jul. 27, 1990)with mercaptan (3) or an acetic acid ester derivative thereof underbasic conditions. The solvent employable in the reaction includespreferably alcohols such as methanol, ethanol and propanol, aproticsolvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile nad tetrahydrofuran. However, in the case wherethe reaction is carried out in the above aprotic solvent using an acetylderivative (4), it is required to coexist alcohols or water. The baseemployable in the reaction includes sodium hydirde, sodium methoxide,sodium ethoxide, lithium methoxide, potassium tertbutoxide, lithiumhydroxide, sodium hydroxide and potassium hydroxide. The amount to beused is 0.1 to 2 molar equivalents based on the compound (2). Mercaptan(3) or the acetic acid derivative thereof (4) is used in 1 to 3 molarequivalents. The reaction temperature is room termperature to 100° C.nad the reaction time is 2 to 10 hours. The compound (Ia) can beobtained by treating the reaction mixture by conventional procedures (anoil obtained by extraction with an organic solvent and then evaporationof the solvent is purified by column chromatography orrecrystallization).

Incidentally, R⁸SH (3) or R⁸SAc (4) used in the above reaction can beobtained according to the process shown below. More specifically, thecompound (3) or (4) in which A in R⁸ is a 1,3-dioxane ring and p=0 canbe prepared using the known compound (5) [reference: O. E. van Lohuizen,P. E. Verkade, Rec. trav. chim., 78, 460 (1959)]as a starting materialaccording to the scheme shown below (with respect to the reactionconditions and the isolation method in each step, see Reference examples3, 4, 5, 6 and 7):

(wherein R², R³, R⁴, R⁵, Ar², q, r and s have the same meanings asdefined above). Among the unsaturated aldehydes (6) used in the abovereaction, the compound (6 a) in which r=0 can be generally obtainedthrough an unsaturated ester (7 a) according to the process shown below(with respect to the reaction conditions and the isolation method ineach step, see Reference examples 8, 9, 10, 20, 21, 22, 23, 33 and 49):

(wherein R², R³, R⁴, R⁵, Ar², q and s have the same meanings as definedabove and DIBAL-H represent diisobutyl aluminum hydride).

Among the unsaturated aldehydes (6), the compound (6 b) in which r=1 or2 can be generally obtained through an unsaturated ester (7 b) accordingto the process shown below (with respect to the reaction conditions andthe isolation method in each step, see Reference examples 44, 45, 46, 47and 48):

(wherein R², R³, R⁴, R⁵, q, r and s have the same meanings as definedabove and DIBAL-H represents diisobutyl aluminum hydride).

Further, the compound (3 b) or (4 b) in which A in R⁸ of R⁸SH (3) orR⁸SAc (4) is a 4- to 7-membered nitrogen-containing heterocyclic group(azetidine, pyrrolidine, piperidine, homopiperidine) and p=1 can beobtained according to the process shown below (with respect to thereaction conditions and the isolation method in each step, see Referenceexamples 16 and 17):

(wherein R², R³, R⁴, R⁵, q, r and s have the same meanings as definedabove, t represents 3, 4, 5 or 6 and Boc representstert-butoxycarbonyl).

The acid chloride (10) used in the above reaction can be obtained bytreating a carboxylic acid, obtained by alkali-decomposing theunsaturated ester (7 a) or (7 b) described above, with thionyl chloride.

Among the compounds having the formula (I) of the present invention, thecompound (Ia) in which R⁰ is a hydrogen atom and n=0 can be alsoobtained according to the process shown below

(wherein Ar¹, R¹ and R⁸ have the same meanings as defined above and Xrepresents a chlorine, bromine or iodine atom, methanesulfonyloxy,benzenesulfonyloxy or toluenesulfonyloxy). More specifically, theprocess is to prepare the desired compound (Ia) by reacting atriazolylmercapto alcohol derivative (11) described in JapaneseUnexamined Patent Publication (KOKAI) No. Hei 3-240778 (Oct. 28, 1991)with an alkylating agent (12) under basic conditions. The solventemployable in the reaction includes methanol, ethanol, propanol,butanol, dimethylformamide, dimethylacetamide, dimethyl sulfoxide,acetonitrile, tetrahydrofuran, dioxane, diethyl ether, acetone, benzene,toluene, xylene, etc. The base employable in the reaction includestriethylamine, diisopropylethylamine, sodium hydride, sodium methoxide,sodium ethoxide, lithium methoxide, potassium tert-butoxide, sodiumhydroxide, potassium hydroxide, etc., and the amount used is 1 to 3molar equivalents based on the compound (11). The alkylating reagent(12) is used in 1 to 3 molar equivalents. The reaction temperature is−50 to 100° C. and the reaction time is 2 to 10 hours. The compound (Ia)can be obtained by treating the reaction mixture by conventionalprocedures (an oil obtained by extraction with an organic solvent andthen evaporation of the solvent is purified by column chromatography orrecrystallization).

The alkylating reagent R⁸-X (12) used in the above reaction can beobtained according to the process shown below. The compound (12 a) inwhich A in R⁸ is a 1,3-dioxane ring and p=0 can be obtained, forexample, by reacting a diol compound (13), obtained by treating theabove compound (5) with an acid in methanol, with the above unsaturatedaldehyde (6) under acidic conditions (Reference example Nos. 56 and 57):

(wherein R², R³, R⁴, R⁵, Ar², q, r and s have the same meanings asdefined above). Further, the compound (12 b) in which A in R⁸ is a 4- to7-membered nitrogen-containing heterocyclic group (azetidine,pyrrolidine, piperidine, homopiperidine) and p=1 can be obtained, forexample, by reacting a compound (14) obtained by treating the abovecyclic amine derivative (8) with HCl, with the above acid chloride (10)in the presence of a base such as triethylamine:

(wherein R², R³, R⁴, R⁵, Ar², q, r, s and t have the same meanings asdefined above).

Among the compounds having the formula (I) of the present invention, thecompound (Ib) in which R⁰ is a hydrogen atom, n=0, p=0 and A is a1,3-dioxane ring can be also prepared according to the process shownbelow:

(wherein Ar¹, Ar², R¹, R², R³, R⁴, R⁵, p, q and r have the same meaningsas defined above). More specifically, the process is to prepare thedesired compound (Ib) by reacting the above epoxide compound (2) with athioacetic acid derivative (15) obtained by the reaction of the aboveknown compound (5) with sodium thioacetate under the same conditions asin the reaction of (2) and (4) to obtain the compound (16), deprotectingthe compound (16) according to conventional procedures such as thetreatment with an acid to obtain the compound (17) and reacting thecompound (17) with the above aldehyde compound (6). The reaction of thecompounds (17) and (6) is usually carried out under acidic conditions.The acid employable here includes, for example, hydrogen chloride,sulfuric acid, nitric acid, boron trifluoride, methanesulfonic acid,benzenesulfonic acid and p-toluenesulfonic acid and the amount of theacid used is 1 to 2 molar equivalents based on (17). The aldehyde (6) isused in 1 to 2 molar equivalents. As the solvent, aprotic solvents suchas methylene chloride, chloroform, 1,2-dichloroethane, benzene, toluene,xylene, diethyl ether and tetrahydrofuran are used. The reaction iscarried out in the range of 0° C. to a boiling point of the solvent andthe reaction time is 2 to 10 hours. While water produced by the reactioncan be removed by azeotropic distillation, molecular sieves may be usedas a dehydrating agent. The compound (Ib) can be obtained byneutralizing the reaction mixture with an aqueous sodiumhydrogencarbonate solution and then treating it by conventionalprocedures (an oil obtained by extraction with an organic solvent andthen evaporation of the solvent is purified by column chromatography orrecrystallization).

Among the compounds of the present invention, the compound (Ic) in whichR⁰ is a hydrogen atom, n=0, p=1 and A is a 4- to 7-memberednitrogen-containing heterocyclic group (azetidine, pyrrolidine,piperidine, homopiperidine) can be obtained according to the processshown below:

(wherein Ar¹, Ar², R¹, R², R³, R⁴, R⁵, q, r, s and t have the samemeanings as defined above and Boc represents tert-butoxy carbonyl). Morespecifically, the process is to prepare the desired compound (Ic) byreacting the above epoxide compound (2) with the mercaptan compound(18), obtained by treating the above thioacetic acid derivative (9) withan alkali, under the same conditions as in the reaction of (2) and (3)to obtain the compound (19), deprotecting (19) by treating it with anacid according to conventional procedures to obtain the compound (20)and reacting the compound (20) with the above acid chloride (10). Thereaction of compounds (20) and (10) is carried out in an inert solventsuch as benzene, toluene, methylene chloride, chloroform ortetrahydrofuran in the presence of an appropriate base by conventionalprocedures (Reference example Nos. 13, 14, 18 and 19).

Among the compounds (I) of the present invention, the compound in whichn=1 or n=2 can be prepared according to the process mentioned below.More specifically, the compound (I) in which n=1 can be prepared byoxidizing the compound (I) in which n=0 obtained by the above process ina solvent using 1 equivalent of an oxidizing agent, and the compound (I)in which n=2 can be prepared by oxidizing it using 2 or more equivalentsof an oxidizing agent. The solvent employable here is not particularlylimited so long as it does not inhibit the reaction and dissolves thestarting materials to some extent and may include preferably ahalogenated hydrocarbon such as methylene chloride and chloroform. Theoxidizing agent employable here may include, for example, peracetic acidand 3-chloroperbenzoic acid. The reaction is carried out at 0 to 50° C.,preferably at room temperature, and the reaction time is usually 30minutes to 2 hours. The compound (I) (n=1 or 2) can be obtained bytreating the reaction mixture according to conventional procedures(after the reaction mixture is washed with aqueous sodiumhydrogencarbonate, the crude product obtained by evaporation of thesolvent is purified by chromatography or recrystallization).

Among the compounds having the formula (I) of the present invention, thecompound (Id) in which R⁰ is lower alkyl and n=0 can be preparedaccording to the process shown below:

(wherein Ar¹, R⁰, R¹ and R⁸ have the same meanings as defined above).More specifically, the desired compound (Id) is prepared by reactingbromoketone (21), obtained according to the procedures described inJapanese Unexamined Patent Publication (KOKAI) No. Hei 7-2802 (Jan. 6,1995), with the above mercaptan (3) or an acetic acid derivative thereof(4) under alkaline conditions to obtain a thioether derivative (22) andreacting (22) with trimethylsulfoxonium iodide and 1,2,4-triazole in thepresence of a base. The solvent used in the reaction of (21) and (3) or(4) includes preferably alcohols such as methanol, ethanol and propanol,and the alkali employable here includes sodium hydroxide, potassiumhydroxide, sodium methoxide and sodium ethoxide. The solvent used in thereaction for converting the thioether derivative (22) to (Id) includespreferably alcohols such as methanol, ethanol, propanol, butanol andt-butanol and aprotic solvents such as dimethylformamide,dimethylacetamide, dimethyl sulfoxide, acetonitrile and tetrahydrofuran.The base used in the reaction includes sodium hydride, sodium methoxide,sodium ethoxide, lithium methoxide, potassium tert-butoxide, lithiumhydroxide, sodium hydroxide and potassium hydroxide, and the amount usedis 2 to 5 molar equivalents based on the compound (22).Trimethylsulfoxonium iodide and 1,2,4-triazole are used in 1 to 2 molarequivalents based on the compound (22), respectively. The reactiontemperature is room temperature to 100° C. and the reaction time is 2 to10 hours. The compound (Id) (n=0) can be obtained by treating thereaction mixture by conventional procedures (a crude product obtained byextraction with an organic solvent and then evaporation of the solventis purified by column chromatography or recrystallization). Among thecompounds (I), the compound (Ie) in which n=0, p=0 and A is a1,3-dioxane ring can be obtained from the compound (23) in which R⁸ is agroup represented by the formula:

in the compound (Id) obtained by the above process through a triol (24)according to the process shown below:

(wherein R⁰ represents lower alkyl and Ar¹, Ar², R¹, R², R³, R⁴, R⁵, q,r and s have the same meanings as defined above). The reactionconditions in the above respective steps are the same as those describedin the reaction of (16)→(17)→(Ib).

The present invention will be explained below in more detail byreferring to Examples, Reference examples, Test examples and Preparationexamples but the scope of the present invention is not limited thereto.

Incidentally, the aldehyde compounds used in Examples are synthesizedaccording to the procedures described in the literature and/or thecitation of the literature in the cases where the literature isindicated in parenthesis. The aldehyde compounds for which theliterature is not indicated are commercially available or can beobtained by the procedures for synthesizing an aldehyde which aredescribed in the literature in the parenthesis of Examples or aredescribed in the citation of the literature or a process according tothe procedures for synthesizing an aldehyde described in Referenceexample of the present specification.

BEST MODE FOR PRACTICING THE INVENTION EXAMPLE 1(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(E)-1-methyl-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxan-5-yl]thio]-2-butanol

In 2 ml of dimethylformamide were dissolved 166 mg (0.48 mmol) oftrans-4-(acetylthio)-2-[(E)-1-methyl-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxaneas described in Reference example 7 and 110 mg (0.44 mmol) of(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane, and 0.15 ml (0.24 mmol) of a 1.6 Msodium methoxide-methanol solution were added thereto under nitrogenatmosphere, followed by stirring of the resulting mixture at 55° C. for6 hours. After cooling, ethyl acetate was added to the reaction mixtureto dilute it and the resulting mixture was washed with a saturatedaqueous NaCl solution. An oil obtained by distilling off the solvent wassubjected to column chromatography using 15 g of silica gel and waseluted by a mixed solvent of hexane-ethyl acetate (2:1) to obtain 180 mg(yield: 74%) of the desired compound as an oil.

NMR spectrum (60 MHz, CDCl₃) δ ppm: 1.19 (3 H, d, J=7 Hz), 1.90 (3 H, d,J=1.5 Hz), 3.34 (1 H, q, J=7 Hz), 3.0-3.9 (3 H, m), 4.1-4.6 (2 H, m),4.80 (1 H, d, J=14 Hz), 4.94 (1 H, s), 5.02 (1 H, d, J=1 Hz), 5.05 (1 H,d, J=14 Hz), 6.4-7.0 (3 H, m), 7.1-7.6 (1 H, m), 7.40 (2 H, d, J=9 Hz),7.62 (2 H, d, J=9 Hz), 7.80 (2 H, s).

EXAMPLE 2(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Reaction and treatment were carried out in the same manner as in Example1 using (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane andtrans-5-(acetylthio)-2-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxaneto obtain the desired compound having a melting point of 73 to 75° C. ina yield of 70%.

Specific rotation [α]_(D) ²⁵ −73.8° (c=1.00, CHCl₃)

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.19 (3 H, d, J=7.3 Hz), 3.34 (1 H,q, J=7.3 Hz), 3.43 (H, tt, J=11.2, 4.6 Hz), 3.65 (1 H, t, J=11.2 Hz),3.67 (1 H, t, J=11.2 Hz), 4.33 (1 H, ddd, J=11.2, 4.6, 2.0 Hz), 4.46 (1H, ddd, J=11.2, 4.6, 2.0 Hz), 4.82 (1 H, d, J=13.8 Hz), 5.03 (1 H, d,J=13.8 Hz), 5.04 (1 H, br s), 5.14 (1 H, d, J=4.6 Hz), 6.25 (1 H, dd,J=15.8, 4.6 Hz), 6.7-7.8 (2 H, m), 6.83 (1 H, d, J=15.8 Hz), 7.3-7.45 (1H, m), 7.49 (2 H, d, J=8.6 Hz), 7.58 (2 H, d, J=8.6 Hz), 7.79 (2 H, s).

EXAMPLE 3(2R,3R)-3-[[Trans-4-[(E)-2-(4-chlorophenyl)vinyl]cyclohexyl]thio]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Reaction and treatment were carried out in the same manner as in Example1 using (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane andtrans-1-(acetylthio)-4-[(E)-2-(4-chlorophenyl)vinyl]cyclohexane toobtain the desired compound having a melting point of 64 to 66° C. in ayield of 31%.

Specific rotation [α]_(D) ²⁵ −84.1° (c=2.69, CHCl₃)

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.16 (3 H, d, J=7.3 Hz), 1.2-1.6 (4H, m), 1.9-2.0 (2 H, m), 2.1-2.25 (3 H, m), 2.70 (1 H, tt, J=11.2, 4.0Hz), 3.36 (1 H, q, J=7.3 Hz), 4.60 (1 H, s), 4.83 (1 H, d, J=13.9 Hz),5.10 (1 H, d, J=13.9 Hz), 6.11 (1 H, dd, J=15.8, 7.3 Hz), 6.32 (1 H, d,J=15.8 Hz), 6.74 (2 H, t-like, J=9 Hz), 7.26 (4 H, s), 7.37 (1 H, td,J=8.6, 6.5 Hz), 7.76 (1 H, s), 7.83 (1 H, s).

EXAMPLE 4(2R,3R)-3-[[Trans-2-[(E)-2-(4-chlorophenyl)vinyl]-1,3-dioxan-5-yl]thio]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

In 14 ml of methylene chloride were dissolved 294 mg (0.82 mmol) of(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Reference example 2 and191 mg (1.15 mmol) of trans-4-chlorocinnamaldehyde [Bull. Chem. Soc.Japan 52 555 (1979)], and 233 mg (1.23 mmol) of p-toluenesulfonic acidmonohydrate and 1.5 g of molecular sieves 4A were added thereto,followed by stirring of the resulting mixture for 1 hour and 15 minutes.An aqueous sodium hydrogencarbonate solution was added to the reactionmixture and the mixture was stirred for 10 minutes, followed by removalof the molecular sieves by filtration. The organic layers were collectedand dried to distil off the solvent under reduced pressure. The thusobtained oil was subjected to column chromatography using 15 g of silicagel and eluted with a mixed solvent hexane-ethyl acetate (3:2) to obtain280 mg (yield: 67%) of the desired title compound, trans isomer (A) asan oil. Further, the oil was eluted with a mixed solvent of hexane-ethylacetate (1:1) to obtain 35 mg (yield: 8%) of the cis isomer (B) as anoil.

Specific rotation (A) [α]_(D) ²⁵ −68° (c=1.22, CHCl₃)

Specific rotation (B) [α]_(D) ²⁵ −80° (c=1.30, CHCl₃)

NMR spectrum (270 MHz, CDCl₃) δ ppm: (A), 1.19 (3 H, d, J=7.3 Hz), 3.34(1 H, q, J=7.3 Hz), 3.41 (1 H, tt, J=11.2, 4.6 Hz), 3.64 (1 H, t, J=11.2Hz), 3.66 (1 H, t, J=11.2 Hz), 4.32 (1 H, ddd, J=11.2, 4.6, 2.6 Hz),4.44 (1 H, ddd, J=11.2, 4.6, 2.6 Hz), 4.82 (1 H, d, J=13.9 Hz), 5.01 (1H, s), 5.04 (1 H, d, J=13.9 Hz), 5.11 (1 H, d, J=4.6 Hz), 6.15 (1 H, dd,J=15.8, 4.6 Hz), 6.7-6.8 (2 H, m), 6.76 (1 H, d, J=15.8 Hz) 7.25-7.45 (5H, m), 7.78 (2 H, s); (B), 1.21 (3 H, d, J=7.3 Hz), 3.11 (1 H, s-like),3.50 (1 H, q, J=7.3 Hz), 4.2-4.4 (4 H, m), 4.88 (1 H, J=14.5 Hz), 4.93(1 H, s), 5.16 (1 H, d, J=14.5 Hz), 5.23 (1 H, d, J=4.6 Hz), 6.21 (1 H,dd, J=16.5, 4.6 Hz), 6.65-6.8 (2 H, m), 6.76 (1 H, d, J=16.5 Hz),7.25-7.45 (5 H, m), 7.77 (1 H, s), 7.80 (1 H, s).

In ethyl acetate was dissolved 54 mg of (A), and 19 mg of oxalic acidwas added to the solution, followed by addition of hexane to theresulting mixture. The precipitated cystal was collected by filtrationto obtain 65 mg of the oxalic acid salt having a melting point of 89 to92° C. The oxalate of (B) having a melting point of 94 to 98° C. wasobtained analogously.

EXAMPLE 5(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(E)-2-(3-pyridyl)vinyl]-1,3-dioxan-5-yl]thiol]-1-(1H-1,2,4-triazol-1-yl)-2-butanol

In 5 ml of methylene chloride were dissolved 120 mg (0.33 mmol) of(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-pyropyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanoland 60 mg (0.45 mmol) of trans-β-(3-pyridyl)acrolein [J. Med. Chem. 18839 (1975)], 190 mg (1.00 mmol) of p-toluenesulfonic acid monohydrateand 1.2 g of molecular sieves 4A were added to the solution, followed bystirring of the resulting mixture for 1 hour and 15 minutes. An aqueoussodium hydrogencarbonate solution was added to the reaction mixture andthe mixture was stirred for 10 minutes, followed by removal of themolecular sieves by filtration and extraction with chloroform. An oilobtained by evaporation of the solvent after drying was subjected tocolumn chromatography using 15 g of silica gel and eluted with a mixedsolvent of hexane-ethyl acetate (1:4 to 1:5) to obtain 82 mg (yield:52%) of the title compound, trans isomer (A) as an oil. Further, the oilwas eluted with ethyl acetate-5% methanol-ethyl acetate to obtain 28 mg(yield: 15%) of the cis isomer (B) having a melting point of 118 to 125°C. as a solid.

NMR spectrum (270MHz, CDCl₃) δ ppm: (A), 1.20 (3H, d, J=7.3Hz), 3.34(1H, q, J=7.3Hz), 3.43 (1H, tt, J=11.2, 4.6Hz), 3.65 (1H, t, J=11.2Hz),3.68 (1H, t, J=11.2Hz), 4.33 (1H, m), 4.46 (1H, m), 4.83 (1H, d,J=13.9Hz), 5.04 (1H, s), 5.04 (1H, d, J=13.9Hz), 5.14 (1H, d, J=4.0Hz),6.25 (1H, dd, J=16.5, 4.0Hz), 6.7-6.8 (2H, m), 6.81 (1H, d, J=16.5Hz),7.29 (1H, dd, J=7.9, 4.6Hz), 7.3-7.45 (1H, m), 7.73 (1H, dt, J=7.9,1Hz), 8.51 (1H, dd, J=4.6, 1Hz), 8.62 (1H, d, J=1Hz); (B), 1.22 (3H, d,J=7.3 Hz), 3.13 (1H, br s), 3.50 (1H, q, J=7.3Hz), 4.2-4.4 (4H, m), 4.88(1H, d, J=13.9Hz), 4.94 (1H, s), 5.17 (1H, d, J=13.9Hz), 5.26 (1H, d,J=4.6Hz), 6.31 (1H, dd, J=16.5, 4.6Hz), 6.65-6.8 (2H, m), 6.81 (1H, d,J=16.5Hz), 7.26 (1H, dd, J=7.9, 4.6Hz), 7.74 (1H, td, J=7.2, 6.6Hz),7.74 (1H, br d, J=7.9Hz), 7.77 (1H, s), 7.80 (1H, s), 8.50 (1H, br d,J=4.6Hz), 8.63 (1H, br s).

EXAMPLE 6(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Reaction and treatment were carried out in the same manner as in Example4 using(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanoland trans-4-(trifluoromethyl)cinnamaldehyde as described in Referenceexample 32 to obtain the desired compound as a major product (yield:62%). Physical data and spectral data coincided with those of thecompound described in Example 2.

EXAMPLE 7(2R,3R)-2-[2,4-Difluorophenyl)-3-[(trans-2-[(E)-2-(4-fluorophenyl)vinyl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Reaction and treatment were carried out in the same manner as in Example4 using (2R,3R)-2-[2,4-Difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanoland trans-4-fluorocinnamaldehyde [Arch. Pharm. 316 574 (1983)] to obtainthe title compound, a major product as an oil in a yield of 66%.

NMR spectrum (60MHz, CDCl₃) δ ppm: 1.20 (3H, d, J=7Hz), 3.1-3.9 (4H, m),4.1-4.6 (2H, m), 4.78 (1H, d, J=14Hz), 4.99 (1H, d, J=1.5Hz), 5.06 (1H,d, J=14Hz), 5.09 (1H, d, J=4Hz), 6.07 (1H, dd, J=16.4Hz), 6.79 (1H, d,J=16Hz), 6.5-7.6 (7H, m), 7.78 (2H, s).

This compound was mixed with 1 equivalent of oxalic acid in a mixedsolvent of ethyl acetate-hexane to obtain an oxalic acid salt crystalhaving a melting point of 132 to 135° C.

EXAMPLE 8(2R,3R)-2-(2,4-Difluorophenyl)-3-[(trans-2-[(E)-2-[2-fluoro-(4-trifluoromethyl)phenyl]vinyl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Reaction and treatment were carried out in the same manner as in Example4 using(2R,3R)-2-[2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanoland trans-2-fluoro-4-(trifluoromethyl)cinnamaldehyde to obtain the titlecompound, a major product as an oil in a yield of 66%.

Specific rotation [α]_(D) ²⁵−72° (c=0.63, CHCl₃)

NMR spectrum (270MHz, CDCl₃) δ ppm: 1.20 (3H, d, J=7.0Hz), 3.34 (1H, q,J=7.0Hz), 3.43 (1H, tt, J=11.3, 4.6Hz), 3.65 (1H, t, J=11.3Hz), 3.68(1H, t, J=11.3Hz), 4.34 (1H, m), 4.46 (1H, m), 4.83 (1H, d, J=14.0Hz),5.04 (d, J=14.0Hz), 5.04 (1H, d, J=1.1Hz), 5.15 (1H, d, J=4.2Hz), 6.36(1H, dd, J=16.3, 4.2Hz), 6.7-6.8 (2H, m), 6.97 (1H, d, J=16.0Hz),7.3-7.45 (3H, m), 7.58 (1H, t, J=7.6Hz), 7.79 (2H, s).

EXAMPLE 9(2R,3R)-2-(2,4-Difluorophenyl)-3-[(trans-2-[(E)-2-(4-(methylsulfonyl)phenyl]vinyl]-1,3-dioxan-5-yl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Reaction and treatment were carried out in the same manner as in Example4 using(2R,3R)-2-[2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanoland trans-4-(methylsulfonyl)cinnamaldehyde to obtain the title compound,a major product as an oil in a yield of 58%.

NMR spectrum (60MHz, CDCl₃+D₂O) δ ppm: 1.20 (3H, d, J=7Hz), 3.00 (3H,s), 3.33 (1H, q, J=7Hz), 3.5-4.0 (3H, m), 4.2-4.8 (2H, m), 4.80 (1H, d,J=14Hz), 5.08 (1H, d, J=14Hz), 5.15 (1H, d, J=4Hz), 6.30 (1H, dd, J=17,4Hz), 6.90 (1H, d, J=17Hz), 6.55-7.0 (2H, m), 7.2-7.6 (1H, m), 7.58 (2H,d, J=8Hz), 7.80 (2H, s), 7.94 (2H, d, J=8Hz).

EXAMPLE 10(2R,3R)-2,4-Difluorophenyl)-3-[[trans-2-[(E)-2-(4-nitrophenyl)vinyl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Reaction and treatment were carried out in the same manner as in Example4 using(2R,3R)-2-[2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thiol]-1-(1H-1,2,4-triazol-5-yl)-2-butanoland trans-4-nitrocinnamaldehyde to obtain the title compound, a majorproduct as an oil in a yield of 40%.

Specific rotation [α]_(m) ²⁵ −64.1° (c=2.43, CHCl₃)

NMR spectrum (270MHz, CDCl₃) δ ppm: 1.19 (3H, d, J=7.3Hz), 3.35 (1H, q,J=7.3 Hz), 3.44 (1H, tt, J=11.2, 4.6Hz), 3.66 (1H, t, J=11.2Hz), 3.68(1H, t, J=11.2Hz), 4.34 (1H, m), 4.46 (1H, m), 4.83 (1H, d, J=13.9Hz),5.04 (1H, d, J=13.9Hz), 5.04 (1H, s), 5.16 (1H, d, J=4.0Hz), 6.32 (1H,dd, J=16.5, 4.0Hz), 6.7-6.8 (2H, m), 6.87 (1H, d, J=16.5Hz), 7.36 (1H,m), 7.53 (2H, d, J=8.6Hz), 7.79 (1H, s), 7.80 (1H, s), 8.19 (2H, d,J=8.6Hz).

This compound was mixed with 1 equivalent of oxalic acid in a mixedsolvent of ethyl acetate-hexane to obtain an oxalic acid salt crystalhaving a melting point of 103 to 105° C.

EXAMPLE 11(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[trans-2-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxan-5-yl]thio]-2-butanol

Reaction and treatment were carried out in the same manner as in Example4 using(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl]thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanoland trans-4-(trifluoromethoxy)cinnamaldehyde as described in Referenceexample 33 to obtain the title compound, a major product as an oil in ayield of 43%.

Specific rotation [α]_(D) ²⁵ −77° (c=0.52 CHCl₃)

NMR spectrum (270MHz, CDCl₃) δ ppm: 1.20 (3H, d, J=7.3Hz), 3.34 (1H, q,J=2.3Hz), 3.42 (1H, tt, J=11.2, 4.6Hz), 3.65 (1H, t, J=11.2Hz), 3.67(1H, t, J=11.2Hz), 4.32 (1H, ddd, J=11.2, 4.6, 2.0Hz), 4.45 (1H, ddd,J=11.2, 4.6, 2.0Hz), 4.83 (1H, d, J=14.5Hz), 5.01 (1H, s), 5.03 (1H, d,J=14.5Hz), 5.12 (1H, d, J=4.0Hz), 6.15 (1H, dd, J=16.5, 4.0Hz), 6.7-6.8(2H, m), 6.79 (1H, d, J=16.5Hz), 7.17 (2H, d, J=8.6Hz), 7.3-7.45 (1H,m), 7.42 (2H, d, J=8.6Hz), 7.79 (2H, s).

EXAMPLE 12(2R,3R)-3-[[Trans-2-[(E)-2-(4-cyanophenyl)vinyl]-1,3-dioxan-5-yl]thio]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Reaction and treatment were carried out in the same manner as in Example4 using(2R,3R)-2-(2,4-difluorophenyl)-3-(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanoland trans-4-cyanocinnamaldehyde [Mol. Cryst. Liq. Cryst. 123 257 (1985)]to obtain the title compound, a major product as an oil in a yield of66%.

Specific rotation [α]_(D) ²⁵−78° (c=0.52 CHCl₃)

NMR spectrum (270MHz, CDCl₃) δ ppm: 1.20 (3H, d, J=7.0Hz), 2.34 (1H, brq, J=7.0Hz), 3.43 (1H, tt, J=11.3, 4.8Hz), 3.65 (1H, t, J=11.3Hz), 3.67(1H, t, J=11.3Hz), 4.33 (1H, m), 4.46 (1H, m), 4.83 (1H, d, J=14.2Hz),5.03 (1H, d, J=1.2Hz), 5.04 (1H, d, J=14.2Hz), 5.14 (1H, d, J=4.1Hz),6.28 (1H, dd, J=16.1, 4.1Hz), 6.7-6.8 (2H, m), 6.82 (1H, d, J=16.1Hz),7.36 (1H, m), 7.49 (2H, d, J=8.3Hz), 7.62 (2H, d, J=8.3Hz), 7.79 (2H,s).

This compound was mixed with 1 equivalent of oxalic acid in a mixedsolvent of ethyl acetate-hexane to obtain an oxalic acid salt crystalhaving a melting point of 164 to 164° C.

EXAMPLE 13(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(E)-2-methyl-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Reaction and treatment were carried out in the same manner as in Example4 using(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanoland trans-β-methyl-4-(trifluoromethyl)cinnamaldehyde to obtain thedesired title compound, a major product as an oil in a yield of 73%.

NMR spectrum (270MHz, CDCl₃) δ ppm: 1.20 (3H, d, J=7.1Hz), 2.16 (3H, s),3.36 (1H, q, J=7.1Hz), 3.41 (1H, tt, J=11.3, 4.6Hz), 3.66 (1H, t,J=11.3Hz), 3.68 (1H, t, J=11.3Hz), 4.32 (1H, m), 4.44 (1H, m), 4.83 (1H,d, J=13.9Hz), 5.03 (1H, s), 5.04 (1H, d, J=13.9Hz), 5.33 (1H, d,J=6.0Hz), 5.83 (1H, br d, J=6.0Hz), 6.7-6.8 (2H, m), 7.3-7.45 (1H, m),7.51 (2H, d, J=8.3Hz), 7.59 (2H, d, J=83. Hz), 7.79 (2H, s).

EXAMPLE 14(2R,3R)-3-[[Trans-2-[(E)-2-(5-chloro-2-thienyl)vinyl]-1,3-dioxan-5-yl]thio]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Reaction and treatment were carried out in the same manner as in Example4 using(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanoland trans-β-[S-chloro-2-thienyl)acrolein [Chem. Abst. 51 1284h (1941)]to obtain the title compound as an oil in a yield of 50%.

Specific rotation [α]_(D) ²⁵−75.7° (c=0.56, CHCl₃)

NMR spectrum (270MHz, CDCl₃) δ ppm: 1.19 (3H, d, J=7.3Hz), 3.33 (1H, q,J=7.3Hz), 3.40 (1H, tt, J=11.2, 4.6Hz), 3.62 (1H, t, J=11.2Hz), 3.64(1H, t, J=11.2Hz), 4.36 (1H, m), 4.42 (1H, m), 4.82 (1H, d, J=13.8Hz),5.02 (1H, br s), 5.03 (1H, d, J=13.8Hz), 5.06 (1H, d, J=4.6Hz), 5.88(1H, dd, J=15.8, 4.6Hz), 6.7-6.85 (3H, m), 6.78 (2H, s), 7.36 (1H, m),7.87 (2H, s).

This compound was mixed with 1 equivalent of oxalic acid in a mixedsolvent of ethyl acetate-hexane to obtain an oxalic acid salt crystalhaving a melting point of 53 to 57° C.

EXAMPLE 15(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl]-3-[[trans-2-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol

Reaction and treatment were carried out in the same manner as in Example4 using(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanoland (2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienal as describedin Reference example 25 to obtain the title compound, a major product asan oil in a yield of 67%.

Specific rotation [α]_(D) ²⁵ −69.8° (c=1.00, CHCl₃)

NMR spectrum (270MHz, CDCl₃) δ ppm: 1.19 (3H, d, J=7.3Hz), 3.33 (1H, q,J=7.3Hz), 3.40 (1H, tt, J=11.2, 4.6Hz), 3.62 (1H, t, J=11.2Hz), 3.64(1H, t, J=11.2Hz), 4.30 (1H, m), 4.42 (1H, m), 4.82 (1H, d, J=13.9Hz),5.01 (1H, s), 5.03 (1H, d, J=13.9Hz), 5.06 (1H, d, J=4.6Hz), 5.84 (1H,dd, J=15.2, 4.6Hz), 6.60 (1H, dd, J=15.2, 10.6Hz), 6.73 (1H, d,J=15.8Hz), 6.7-6.8 (2H, m), 6.85 (1H, dd, J=15.8, 10.6Hz), 7.3-7.45 (1H,m), 7.49 (2H, d, J=8.6Hz), 7.56 (2H, d, J=8.6Hz), 7.78 (2H, s).

EXAMPLE 16(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(1E,3E)-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Reaction and treatment were carried out in the same manner as in Example4 using(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanoland (2E,4E)-5-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-pentadienal asdescribed in Reference example 32 to obtain the title compound having amelting point of 75 to 85° C. (crystallization from a mixed solvent ofhexane-ether), a major product as a powder in a yield of 60%.

Specific rotation [α]_(D) ²⁵ −69° (c=0.56, CHCl₃)

NMR spectrum (270MHz, CDCl₃) δ ppm: 1.18 (3H, d, J=7.0Hz), 3.33 (1H, q,J=7.0Hz), 3.39 (1H, tt, J=11.3, 4.8Hz), 3.62 (1H, t, J=11.1Hz), 3.64(1H, t, J=11.3Hz), 4.30 (1H, m), 4.35 (2H, br t, J=11.8Hz), 4.41 (1H,m), 4.82 (1H, d, J=14.1Hz), 4.99 (1H, d, J=1.6Hz), 5.03 (1H, d,J=14.1Hz), 5.04 (1H, d, J=4.6Hz), 5.75 (1H, dd, J=15.7, 4.6Hz), 6.06(1H, tt, J=53.0, 5.1Hz), 6.56 (1H, dd, J=15.7, 10.2Hz), 6.57 (1H, d,J=15.0Hz), 6.68 (1H, dd, J=15.0, 10.2Hz), 6.7-6.8 (2H, m), 6.88 (2H, d,J=8.7Hz), 7.3-7.4 (1H, m), 7.3 (2H, d, J=8.7Hz), 7.79 (2H, s).

EXAMPLE 17(2R,3R)-3-[(Trans-2-[(1E,3E)-4-(6-chloro-3-pyridyl)-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Reaction and treatment were carried out in the same manner as in Example4 using(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanoland (2E,4E)-5-(6-chloro-3-pyridyl)-2,4-pentadienal as described inReference example 38 to obtain the title compound having a melting pointof 88 to 90° C., a major product as a crystalline solid in a yield of69%.

Specific rotation [α]_(D) ²⁵−74° (c=0.59, CHCl₃)

NMR spectrum (270MHz, CDCl₃) δ ppm: 1.19 (3H, d, J=7.1Hz), 3.33 (1H, q,J=7.1Hz), 3.40 (1H, tt, J=11.3, 4.7Hz), 3.62 (1H, t, J=11.3Hz), 3.64(1H, t, J=11.3Hz), 4.30 (1H, m), 4.42 (1H, m), 4.82 (1H, d, J=14.3Hz),5.00 (1H, s), 5.03 (1H, d, J=14.3Hz), 5.05 (1H, d, J=4.2Hz), 5.84 (1H,dd, J=15.1, 4.2Hz), 6.56 (1H, d, J=15.5Hz), 6.58 (1H, dd, J=15.1,10.5Hz), 6.7-6.8 (2H, m), 6.80 (1H, dd, J=15.5, 10.5Hz), 7.28 (1H, d,J=8.3Hz), 7.3-7.4 (1H, m), 7.70 (1H, dd, J=8.3, 2.5Hz), 7.79 (2H, s),8.37 (1H, d, J=2.5Hz).

EXAMPLE 18(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-[(1E,3Z)-4-(4-chlorophenyl)-5,5,5-trifluoro-1,3-pentadien-1-yl]-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Reaction and treatment were carried out in the same manner as in Example4 using(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanoland (2E,4Z)-5-(4-chlorophenyl)-6,6,6-trifluoro-2,4-hexadienal asdescribed in Reference example 52 to obtain the title compound, a majorproduct as an oil in a yield of 31%.

Specific rotation [α]_(D) ²⁵ −59.4° (c=0.90, CHCl₃) NMR spectrum(270MHz, CDCl₃) δ ppm: 1.19 (3H, d, J=7.3Hz), 3.33 (1H, br q, J=7.3Hz),3.40 (1H, tt, J=11.2, 4.6Hz), 3.61 (1H, t, J=11.2Hz), 3.64 (1H, t,J=11.2Hz), 4.31 (1H, m), 4.43 (1H, m), 4.82 (1H, d, J=13.9Hz), 5.02 (1H,s), 5.03 (1H, d, J=13.9Hz), 5.09 (1H, d, J=4.6Hz), 5.96 (1H, dd, J=15.2,4.6Hz), 6.50 (1H, J=11.9Hz), 6.7-6.8 (2H, m), 6.9-7.1 (1H, m), 7.25-7.4(5H, m), 7.79 (2H, s).

EXAMPLE 19(2R,3R)-2-(2,4-Difluorophenyl)-3-[[Trans-2-[(1E,3E)-2-Methyl-4-[4-(Trifluoromethyl)Phenyl]-1,3-Butadien-1-yl]-1,3-Dioxan-5-yl]Thio]-1-(1H-1,2,4-Triazol-1-yl)-2-Butanol

Reaction and treatment were carried out in the same manner as in Example4 using(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanoland (2E,4E)-3-methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienal asdescribed in Reference example 10 to obtain the title compound, a majorproduct as an oil in a yield of 70%.

Specific rotation [α]_(D) ²⁵ −68° (c=0.50, CHCl₃)

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.27 (3H, d, J=7.1 Hz), 1.99 (3H,s), 3.34 (1H, q, J=7.1 Hz), 3.39 (1H, tt, J=11.3, 4.8 Hz), 3.64 (1H, t,J=11.3 Hz), 3.66 (1H, t, J=11.3 Hz), 4.30 (1H, m), 4.41 (1H, m), 4.83(1H, d, J=14.1 Hz), 5.01 (1H, s), 5.04 (1H, d, J=14.1 Hz), 5.32 (1H, d,J=6.2 Hz), 5.66 (1H, d, J=6.2 Hz), 6.66 (1H, d, J=16.1 Hz), 6.7-6.8 (2H,m), 6.86 (1H, d, J=16.1 Hz), 7.3-7.4 (1H, m), 7.51 (2H, d, J=8.4 Hz),7.57 (2H, d, J=8.4 Hz), 7.78 (2H, s).

EXAMPLE 20(2R,3R)-2-(2,4-Difluorophenyl)-3-[[Trans-2-[(1E,3E)-3-Methyl-4-[4-(Trifluoromethyl)Phenyl]-1,3-Butadien-1-yl]-1,3-Dioxan-5-yl]Thio]-1-(1H-1,2,4-Triazol-1-yl)-2-Butanol

Reaction and treatment were carried out in the same manner as in Example4 using(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanoland (2E,4E)-4-methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienal toobtain the title compound, a major product as an oil in a yield of 69%.

Specific rotation [α]_(D) ²⁵ −63.4° (c=1.07, CHCl₃)

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.19 (3H, d, J=7.0 Hz), 2.00 (3H,t, J=11.2 Hz), 3.66 (1H, t, J=11.2 Hz), 4.31 (1H, m), 4.43 (1H, m), 4.83(1H, d, J=14.2 Hz), 5.01 (1H, s), 5.04 (1H, d, J=14.2 Hz), 5.09 (1H, d,J=4.6 Hz), 5.81 (1H, dd, J=16.0, 4.6 Hz), 6.60 (1H, s), 6.63 (1H, d,J=16.0 Hz), 6.7-6.8 (2H, m), 7.3-7.4 (1H, m), 7.38 (2H, d, J=8.2 Hz),7.59 (2H, d, J=8.2 Hz), 7.79 (2H, s).

EXAMPLE 21(2R,3R)-2-(2,4-Difluorophenyl)-3-[[1-[(E)-4-(Trifluoromethoxy)Cinnamoyl]Piperidin-4-yl]Thio]-1-(1H-1,2,4-Triazol-1-yl)-2-Butanol

[Process A]

To a mixture of 150 mg (0.340 mmol) of(2R,3R)-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-3-[(piperidin-4-yl)thio]-2-butanoldihydrochloride as described in Reference example 14 and 3 ml ofdichloromethane were added 142 μl (1.02 mmol) of triethylamine at 0° C.under nitrogen atmosphere and, after 5 minutes, 128 mg (0.510 mmol) of(E)-4-(trifluoromethoxy)cinnamoyl chloride. The mixture was stirred atthe same temperature for 30 minutes and the solvent was distilled off,and then ethyl acetate was added to the thus obtained residue, followedby washing of the mixture with an aqueous NaCl solution. The solvent wasdistilled off and the residue was subjected to silica gel columnchromatography, followed by elution with ethyl acetate to obtain 160 mg(yield: 81%) of the title compound as a colorless foam.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.19 (3H, d, J=7.0 Hz), 1.6-1.8(2H, m), 2.0-2.1 (2H, m), 3.0-3.2 (2H, m), 3.35 (1H, q, J=7.0 Hz),3.2-3.4 (1H, m), 4.0-4.1 (1H, m), 4.2-4.3 (1H, m, 4.83 (1H, s), 4.83(1H, d, J=14.0 Hz), 5.09 (1H, d, J=14.0 Hz), 6.7-6.8 (2H, m), 6.87 (1H,d, J=15.5 Hz), 7.22 (2H, d, J=8.5 Hz), 7.3-7.4 (1H, m), 7.55 (2H, d,J=8.5 Hz), 7.65 (1H, d, J=15.5 Hz, 7.78 (1H, s), 7.82 (1H, s). IRspectrum υ_(max) ^(KBr)cm⁻¹: 3421, 1695, 1686, 1617, 1591. Mass spectrumm/e: 582, 563, 522, 500, 427, 359, 299, 258, 215, 187, 144, 101, 82.

[Process B]

In 4 ml of dimethylformamide were dissolved 327 mg (0.875 mmol) of4-(acetylthio)-1-[(E)-4-(trifluoromethoxy)cinnamoyl]piperidine asdescribed in Reference example 16 and 200 mg (0.796 mmol) of(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane,and 129 μl (0.613 mmol) of a 28% sodium methoxide-methanol solution wereadded to the mixture under nitrogen atmosphere, followed by stirring ofthe resulting mixture at 50° C. for 3 hours. After cooling, ethylacetate was added to the reaction mixture to dilute it and washed withwater and then a saturated aqueous NaCl solution. The oil obtained byevaporation of the solvent was subjected to silica gel columnchromatography and eluted with ethyl acetate to obtain 275 mg (yield:59%) as a colorless foam. The present compound was identified as thecompound obtained according to the [Process A] by means of each spectrumof NMR, IR and MS.

EXAMPLE 22(2R,3R)-2-(2,4-Difluorophenyl)-3-[[1-((E)-4-Methylcinnamoyl)Piperidin-4-yl]Thio]-1-(1H-1,2,4-Triazol-1-yl)-2-Butanol

A colorless foam obtained from (E)-4-methylcinnamoyl chloride (Can. J.Chem. 45 1001 (1967)] according to [Process A] of Example 21.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.19 (3H, d, J=7.0 Hz), 1.6-1.8(2H, m), 2.0-2.2 (2H, m), 2.37 (3H, s), 3.0-3.2 (2H, m), 3.2-3.4 (1H,m), 3.35 (1H, q, J=7.0 Hz), 4.0-4.2 (1H, m), 4.4-4.6 (1H, m), 4.83 (1H,d, J=13.9 Hz), 4.84 (1H, s), 5.09 (1H, d, J=13.9 Hz), 6.7-6.8 (2H, m),6.85 (1H, d, J=15.5 Hz), 7.18 (2H, d, J=8.3 Hz), 7.3-7.4 (1H, m), 7.43(2H, d, J=8.3 Hz), 7.65 (1H, d, J=15.5 Hz), 7.77 (1H, s), 7.82 (1H, s).IR spectrum υ_(max) ^(KBr)cm⁻¹: 3333, 1645, 1599. Mass spectrum m/e:512, 510, 452, 430, 425, 367, 357, 289, 229, 224, 188, 145, 117, 82.

EXAMPLE 23(2R,3R)-2-(2,4-Difluorophenyl)-3-[[1-((E)-4-Nitrocinnamoyl)Piperidin-4-yl]Thio]-1-(1H-1,2,4-Triazol-1-yl)-2-Butanol

A slightly yellow foam obtained from (E)-4-nitrocinnamoyl chlorideaccording to [Process A] of Example 21.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.26 (3H, d, J=6.6 Hz), 1.6-1.9(2H, m), 2.1-2.3 (2H, m), 3.1-3.3 (2H, m), 3.3-3.5 (1H, m), 3.42 (1H, q,J=6.6 Hz), 4.0-4.2 (1H, m), 4.4-4.6 (1H, m), 4.89 (1H, d, J=13.9 Hz),4.92 (1H, s), 5.15 (1H, d, J=13.9 Hz), 6.7-6.9 (2H, m), 7.10 (1H, d,J=15.5 Hz), 7.4-7.5 (1H, m), 7.73 (2H, d, J=8.9 Hz), 7.75 (1H, d, J=15.5Hz), 7.86 (2H, d, J=8.9 Hz), 8.29 (1H, s), 8.32 (1H, s). IR spectrumυ_(max) ^(KBr)cm⁻¹: 3361, 1649, 1612, 1518, 1345. Mass spectrum m/e:544, 525, 513, 483, 461, 388, 365, 284, 260, 224, 219, 176, 144, 130,82.

EXAMPLE 24(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-Triazol-1-yl)-3-[[1-[(2E,4E)-5-[4-(Trifluoromethoxy)Phenyl]-2,4-Pentadienoyl]Piperidin-4-yl]Thio]-2-Butanol

A colorless foam obtained from(2E,4E)-5-[4-(trifluoromethoxy)phenyl]-2,4-pentadienoyl chlorideaccording to [Process A] of Example 21.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.19 (3H, d, J=6.6 Hz), 1.5-1.8(2H, m), 2.0-2.2 (2H, m), 3.0-3.3 (3H, m), 3.34 (1H, q, J=6.6 Hz),3.9-4.1 (1H, m), 4.3-4.5 (1H, m), 4.83 (1H, d, J=13.9 Hz), 4.82 (1H, s),5.08 (1H, d, J=13.9 Hz), 6.50 (1H, d, J=14.5 Hz), 6.7-6.8 (2H, m),6.8-6.9 (2H, m), 7.20 (2H, d, J=8.9 Hz), 7.3-7.5 (2H, m), 7.47 (2H, d,J=8.9 Hz), 7.78 (1H, s), 7.82 (1H, s). IR spectrum υ_(max) ^(KBr)cm⁻¹:3395, 1639, 1616, 1596. Mass spectrum m/e: 608, 589, 548, 526, 453, 433,385, 325, 241, 224, 213, 144, 127, 82.

EXAMPLE 25(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-Triazol-1-yl)-3-[[1-[(E)-3-(Pyridin-4-yl)-Acryloyl]Piperidin-4-yl]Thio]-2-Butanol

A colorless foam obtained from4-acetylthio-1-[(E)-3-(pyridin-4-yl)-acryloyl]piperidine according to[Process B] of Example 21.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.20 (3H, d, J=6.6 Hz), 1.6-1.8(2H, m), 2.0-2.2 (2H, m), 3.0-3.2 (2H, m), 3.35 (1H, q, J=6.6 Hz),3.2-3.4 (1H, m), 3.9-4.1 (1H, m), 4.3-4.5 (1H, m), 4.83 (1H, d, J=14.5Hz), 4.86 (1H, s), 5.09 (1H, d, J=14.5 Hz), 6.7-6.8 (2H, m), 7.06 (1H,d, J=15.2 Hz), 7.3-7.4 (1H, m), 7.37 (2H, d, J=5.9 Hz), 7.57 (1H, d,J=15.2 Hz), 7.78 (1H, s), 7.81 (1H, s), 8.64 (2H, d, J=5.9 Hz). IRspectrum υ_(max) ^(KBr)cm⁻¹: 3420, 1651, 1615, 1598. Mass spectrum m/e:499, 439, 417, 410, 365, 344, 307, 275, 247, 216, 144, 132, 104, 82.

EXAMPLE 26(2R,3R)-2-(2,4-Difluorophenyl)-3-[[1-(E)-4-(Trifluoromethoxy)Cinnamoyl]Azetidin-3-yl]Thio]-1-(1H-1,2,4-Triazol-1-yl)-2-Butanol

A slightly yellow foam obtained from(2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[(azetidin-3-yl]thio]-2-butanoldihydrochloride according to [Process A] of Example 21.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.17 (3H, d, J=7.1 Hz), 3.32 (1H,q, J=7.1 Hz), 4.0-4.3 (3H, m), 4.5-4.6 (1H, m), 4.6-4.7 (1H, m), 4.86(1H, d, J=14.2 Hz), 5.05 (1H, d, J=14.2 Hz), 5.09 (1H, s), 6.43 (1H, d,J=15.7 Hz), 6.7-6.8 (2H, m), 7.22 (2H d, J=8.2 Hz), 7.3-7.4 (1H, m),7.56 (2H, d, J=8.2 Hz), 7.65 (1H, d, J=15.7 Hz), 7.79 (1H, s), 7.81 (1H,s). IR spectrum υ_(max) ^(KBr)cm⁻¹: 3376, 1656. Mass spectrum m/e: 554,535, 472, 384, 331, 271, 224, 215, 187, 127, 87.

EXAMPLE 27(2R,3R)-2-(2,4-Difluorophenyl)-3-[[Trans-2[(1E,3E)-4-(2,4-Difluorophenyl)-1,3-Butadien-1-yl]-1,3-Dioxan-5-yl]Thio]-1-(1H-1,2,4-Triazol-1-yl)-2-Butanol

Reaction was carried out in the same manner as in Example 4 using(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanoland (2E,4E)-5-(2,4-difluorophenyl)-2,4-pentadienal to obtain the titlecompound, a major product as an oil in a yield of 61%.

Specific rotation [α]_(D) ²⁵−79.1° (c=1.04, CHCl₃)

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.18 (3H, d, J=7.0 Hz), 3.33 (1H,q, J=7.0 Hz), 3.39 (1H, tt, J=11.3, 4.6 Hz), 3.62 (1H, t, J=11.3 Hz),3.64 (1H, t, J=11.3 Hz), 4.30 (1H, m), 4.41 (1H, m), 4.82 (1H, d, J=14.0Hz), 5.00 (1H, s), 5.03 (1H, d, J=14.0 Hz), 5.05 (1H, d, J=4.6 Hz), 5.79(1H, dd, J=15.2, 4.6 Hz), 6.58 (1H, dd, J=15.2, 9.5 Hz), 6.65-6.9 (6H,m), 7.3-7.5 (2H, m), 7.79 (2H, s).

EXAMPLE 28(2R,3R)-2-(2,4-Difluorophenyl)-3-[[Trans-2-[(1E,3E)-4-[6-(2,2,3,3-Tetrafluoropropoxy)-3-Pyridyl]-1,3-Butadien-1-yl]-1,3-Dioxan-5-yl]Thio]-1-(1H-1,2,4-Triazol-5-yl)-2-Butanol

In 11 ml of methylene chloride were dissolved 404 mg (1.12 mmol) of(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanoland 501 mg (1.73 mmol) of(2E,4E)-5-[6-(2,2,3,3-tetrafluoropropoxy)-3-pyridyl]-2,4-pentadienal asdescribed in Reference example 37, and 320 mg (1.68 mmol) ofp-toluenesulfonic acid monohydrate and 4 g of molecular sieves 4A wereadded to the solution, followed by stirring of the resulting mixture atroom temperature for 1 hour. The reaction mixture was poured into 20 mlof a 3% aqueous sodium hydrogencarbonate solution under ice-cooling andthe mixture was stirred for 5 minutes. Then, the molecular sieves wasremoved by filtration and the organic layer was collected by fractions,followed by drying and evaporation of the solvent under reducedpressure. 908 mg of the thus obtained oil were subjected to columnchromatography using 19 g of silica gel and eluted with a mixed solventof hexane-ethyl acetate (1:1) to obtain 448 mg (yield: 63%) of thedesired title compound as an oil.

Specific rotation [α]_(D) ²⁵ −58.6° (c=0.52, CHCl₃)

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.19 (3H, d, J=7.0 Hz), 3.33 (1H,q, J=7.0 Hz), 3.39 (1H, tt, J=11.2, 4.8 Hz), 3.62 (1H, t, J=11.2 Hz),3.64 (1H, t, J=11.2 Hz), 4.30 (1H, ddd, J=11.2, 4.7, 2.1 Hz), 4.42 (1H,ddd, J=11.2, 4.7, 2.1 Hz), 4.74 (2H, brt, J=12.8 Hz), 4.82 (1H, d,J=13.9 Hz), 5.01 (1H, s), 5.03 (1H, d, J=13.9 Hz), 5.05 (1H, d, J=4.5Hz), 5.78 (1H, d, J=15.5, 4.5 Hz), 6.01 (1H, tt, J=53.1, 4.6 Hz),6.51-6.62 (2H, m), 6.65-6.78 (3H, m), 6.81 (1H, d, J=8.6 Hz), 7.35 (1H,m), 7.74 (1H, dd, J=8.6, 2.3 Hz), 7.79 (2H, s), 8.11 (1H, d, J=2.3 Hz).

EXAMPLE 29(2R,3R)-2-(2,4-Difluorophenyl)-3-[[Trans-2-[(1E,3E)-1-Methyl-4-[4-(Trifluoromethyl)Phenyl]-1,3-Butadien-1-yl]-1,3-Dioxan-5-yl]Thio]-1-(1H-1,2,4-Triazol-1-yl)-2-Butanol

Reaction was carried out in the same manner as in Example 4 using(2R,3R)-2-(2,4-diphenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanoland (2E,4E)-2-methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienal toobtain the title compound, a major product as an oil in a yield of 31%.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.19 (3H, d, J=7.3 Hz), 1.94 (3H,s), 3.34 (1H, q, J=7.3 Hz), 3.39 (1H, tt, J=11.2, 4.6 Hz), 3.36 (1H, t,J=11.2 Hz), 3.65 (1H, t, J=11.2 Hz), 4.33 (1H, m), 4.44 (1H, m), 4.83(1H, d, J=13.9 Hz), 4.89 (1H, s), 5.02 (1H, s), 5.04 (1H, d, J=13.9 Hz),6.41 (1H, d, J=11.2 Hz), 6.62 (1H, d, J=15.8 Hz), 6.7-6.8 (2H, m), 7.09(1H, dd, J=15.8, 11.2 Hz), 7.36 (1H, m), 7.50 (2H, d, J=8.6 Hz), 7.56(2H, d, J=8.6 Hz), 7.79 (1H, s), 7.80 (1H, s).

EXAMPLE 30(RS)-3-Methyl-1-(1H-1,2,4-Triazol-1-yl)-2-[4-(Trifluoromethyl)Phenyl]-3-[[Trans-2-[(E)-2-[4-(Trifluoromethyl)Phenyl]Vinyl]-1,3-Dioxan-5-yl]Thio]-2-Butanol

Reaction was carried out in the same manner as in Example 4 using(RS)-3-[(1,3-dihydroxy-2-propyl)thio]-3-methyl-2-[4-(trifluoromethyl)phenyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanolas described in Reference example 55 andtrans-4-(trifluoromethyl)cinnamaldehyde as described in Referenceexample 22 to obtain the title compound as a colorless foam.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.36 (3H, s), 1.37 (3H, s), 3.5-3.7(3H, m), 4.2-4.3 (1H, m), 4.4-4.5 (1H, m), 5.02 (2H, s), 5.11 (1H, d,J=4.1 Hz), 5.44 (1H, s), 6.25 (1H, dd, J=16.2, 4.1 Hz), 6.84 (1H, d,J=16.2 Hz), 7.4-7.6 (8H, m), 7.70 (1H, s), 7.93 (1H, s). IR spectrumυ_(max) (KBr) cm⁻¹: 3404, 1618, 1508, 1328. Mass spectrum m/e: 587, 568,331, 298, 256, 201, 159, 131.

EXAMPLE 31(RS)-3-Methyl-1-(1H-1,2,4-Triazol-1-yl)-2-[4-(Trifluoromethyl)Phenyl]-3-[[Trans-2-[(1E,3E)-4-[(Trifluoromethyl)Phenyl]-1,3-Butadien-1-yl]-1,3-Dioxan-5-yl]Thio]-2-Butanol

Reaction was carried out in the same manner as in Example 4 using(RS)-3-[(1,3-dihydroxy-2-propyl)thio]-3-methyl-2-[4-(trifluoromethyl)phenyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanolas described in Reference example 55 and(2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienal as described inReference example 25 to obtain the title compound, a major product as acolorless foam.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.36 (3H, s), 1.37 (3H, s), 3.4-3.7(3H, m), 4.2-4.3 (1H, m), 4.4-4.5 (1H, m), 5.01 (2H, s), 5.02 (1H, d,J=4.3 Hz), 5.39 (1H, s), 5.83 (1H, dd, J=15.2, 4.3 Hz), 6.59 (1H, dd,J=15.2, 10.7 Hz), 6.63 (1H, d, J=15.8 Hz), 6.85 (1H, dd, J=15.8, 10.7Hz), 7.4-7.6 (8H, m), 7.73 (1H, s), 7.93 (1H, s). IR spectrum υ_(max)(KBr) cm⁻¹: 3398, 1679, 1619, 1328, 1126. Mass spectrum m/e: 614, 541,494, 478, 406, 348, 256, 211.

EXAMPLE 32(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-Triazol-1-yl)-3-[[Trans-2-[(1E,3E)-4-[4-(Trifluoromethylthio)Phenyl]-1,3-Butadien-1-yl]-1,3-Dioxan-5-yl]Thio]-2-Butanol

Reaction was carried out in the same manner as in Example 4 using(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanoland (2E,4E)-5-[4-(trifluoromethylthio)phenyl]-2,4-pentadienal to obtainthe title compound, a major product as a colorless foam.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.19 (3H, d, J=7.1 Hz), 3.3-3.5(2H, m), 3.62 (1H, t, J=11.4 Hz), 3.64 (1H, t, J=11.4 Hz), 4.31 (1H,ddd, J=11.4, 4.7, 2.1 Hz), 4.42 (1H, ddd, J=11.4, 4.7, 2.1 Hz), 4.83(1H, d, J=14.1 Hz), 5.01 (1H, s), 5.03 (1H, d, J=14.1 Hz), 5.06 (1H, d,J=4.5 Hz), 5.83 (1H, dd, J=15.7, 4.5 Hz), 6.60 (1H, dd, J=15.7, 10.3Hz), 6.62 (1H, d, J=15.7 Hz), 6.7-6.8 (2H, m), 6.84 (1H, dd, J=15.7,10.3 Hz), 7.3-7.4 (1H, m), 7.44 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3Hz), 7.79 (2H, s).

IR spectrum υ_(max) (KBr) cm⁻¹: 3389, 1621, 1680, 1621, 1501, 1117.

Mass spectrum m/e: 599, 580, 557, 530, 500, 438, 388, 376, 346, 284,258, 224, 183.

EXAMPLE 33 (2R*,3R*)-3-[[Trans-2-[[1E,3E)-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1,3-butadien-1-yl]1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-2-butanol

Reaction was carried out in the same manner as in Example 1 using(2R*,3R*)-3-[[dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-5-yl)-2-[4-(trifluoromethyl)phenyl]-2-butanoland (2E,4E)-5-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-pentadienal asdescribed in Reference example 32 to obtain the title compound, a majorproduct as an oil.

NMR spectrum (270 MHYz, CDCl₃) δ ppm: 1.22 (3H, d, J=6.6 Hz), 3.16 (1H,q, J=6.6 Hz), 3.34 (1H, tt, J=11.2, 4.6 Hz), 3.58 (1H, t, J=11.2 Hz),3.61 (1H, t, J=11.2 Hz), 4.27 (1H, m), 4.35 (2H, br t, J=11.9 Hz), 4.39(1H, m ), 4.57 (1H, d, J=13.9 Hz), 4.77 (1H, s), 5.02 (1H, d, J=4.6 Hz),5.03 (1H, d, J=13.9 Hz), 5.72 (1H, dd, J=15.8, 4.6 Hz), 6.05 (1H, tt,J=52.8, 5.3 Hz), 6.5-6.75 (3H, m), 6.88 (2H, d, J=8.6 Hz), 7.36 (2H, d,J=8.6 Hz), 7.39 (2H, d, J=8.6 Hz), 7.54 (2H, d, J=8.6 Hz), 7.71 (1H, s),7.83 (1H, s).

EXAMPLE 34(2R*,3R*)-1-(1H-1,2,4-Triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-3-[[trans-2-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol

Reaction was carried out in the same manner as in Example 1 using(2R*,3R*)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane andtrans-5-(acetylthio)-2-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxaneto obtain the title compound as an oil in a yield of 71%.

NMR spectrum (270 MHz, CDCL₃) δ ppm: 1.22 (3H, d, J=7.0 Hz), 3.17 (1H,q, J=7.0 Hz), 3.36 (1H, tt, J=11.3, 4.7 Hz), 3.59 (1H, t, J=11.3 Hz),3.62 (1H, t, J=11.3 Hz), 4.27 (1H, ddd, J=11.3, 4.7, 2.2 Hz), 4.39 (1H,ddd, J=11.3, 4.7, 2.2 Hz), 4.57 (1H, d, J=14.0 Hz), 4.80 (1H, s), 5.03(1H, d, J=14.0 Hz), 5.05 (1H, d, J=4.5 Hz), 5.83 (1H, dd, J=15.3, 4.5Hz), 6.59 (1H, dd, J=15.3, 10.7 Hz), 6.64 (1H, d, J=15.3 Hz), 6.85 (1H,dd, J=15.3, 10.7 Hz), 7.39 (2H, d, J=8.4 Hz), 7.49 (2H, d, J=8.3 Hz),7.54 (2H, d, J=8.3 Hz), 7.57 (2H, d, J=8.4 Hz), 7.71 (1H, s), 7.83 (1H,s).

EXAMPLE 35(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[trans-2-[(1E,3E)-4-[4-(trifluoromethylsulfinyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol

Reaction was carried out in the same manner as in Example 4 using(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-5-yl)-2-butanoland (2E,4E)-5-[4-(trifluoromethylsulfinyl)phenyl]-2,4-pentadienal toobtain the title compound, a major product as a colorless foam.

NMR spectrum (270 MHz, CDCL₃) δ ppm: 1.19 (3H, d, J=7.0 Hz), 3.3-3.5(2H, m), 3.62 (1H, t, J=11.3 Hz), 3.64 (1H, t, J=11.3 Hz), 4.30 (1H,ddd, J=11.3, 4.8, 2.3 Hz), 4.42 (1H, ddd, J=11.3, 4.8, 2.3 Hz), 4.83(1H, d, J=14.1 Hz), 5.01 (1H, s), 5.03 (1H, d, J=14.1 Hz), 5.06 (1H, d,J=4.5 Hz), 5.83 (1H, dd, J=15.9, 4.5 Hz), 6.60 (1H, dd, J=15.9, 10.6Hz), 6.62 (1H, d, J=15.9 Hz), 6.7-6.8 (2H, m), 6.84 (1H, dd, J=15.9,10.6 Hz), 7.3-7.4 (1H, m), 7.44 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3Hz), 7.79 (2H, s).

Mass spectrum m/e: 616, 600, 547, 400, 370, 342, 284, 252, 224, 183.

EXAMPLE 36(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[trans-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]cyclohexyl]thio]-2-butanol

Reaction was carried out in the same manner as in Example 1 using(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxiraneandtrans-1-(acetylthio)-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]cyclohexaneas described in Reference example 43 to obtain the title compound havinga melting point of 74 to 76° C. in a yield of 59%.

Specific rotation [α]_(D) ²⁵−83° (c=0.90, CHCl₃)

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.1-1.6 (4H, m), 1.17 (3H, d, J=7Hz), 1.8-2.0 (2H, m), 2.0-2.2 (2H, m), 2.69 (1H, tt, J=12.3 Hz), 3.35(1H, q, J=7 Hz), 4.64 (1H, s, OH), 4.83 (1H, d, J=15 Hz), 5.10 (1H, d,J=15 Hz), 5.83 (1H, dd, J=15, 7 Hz), 6.22 (1H, dd, J=15, 10 Hz), 6.48(1H, d, J=15 Hz), 6.74 (1H, t, J=8 Hz), 6.81 (1H, dd, J=15, 10 Hz),7.1-7.5 (2H, m), 7.45 (2H, d, J=8 Hz), 7.54 (2H, d, J=8 Hz), 7.76 (1H,s), 7.84 (1H, s).

IR spectrum υ_(max) (CHCl₃) cm⁻¹: 1615, 1500, 1325, 1125, 1068.

Mass spectrum m/e: 563, 544, 340, 310, 277, 224, 159, 127.

EXAMPLE 37(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[trans-2-[(1E,3E,5E)-6-[4-(trifluoromethyl)phenyl]-1,3,5-hexatrien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol

Reaction was carried out in the same manner as in Example 4 using(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanoland (2E,4E,6E)-7-[4-(trifluoromethyl)phenyl]-2,4,6-heptatrienal asdescribed in Reference example 28 to obtain the title compound, a majorproduct as an oil in a yield of 65%.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.18 (3H, d, J=6.6 Hz), 3.33 (1H,q, J=6.6 Hz), 3.38 (1H, tt, J=11.2, 4.6 Hz), 3.61 (1H, t, J=11.2 Hz),3.63 (1H, t, J=11.2 Hz), 4.29 (1H, m), 4.40 (1H, m), 4.83 (1H, d, J=14.5Hz), 5.00 (1H, s), 5.02 (1H, d, J=14.5 Hz), 5.03 (1H, d, J=4.6 Hz), 5.74(1H, dd, J=15.2, 4.6 Hz), 6.35-6.55 (3H, m), 6.59 (1H, d, J=15.2 Hz),6.7-6.8 (2H, m), 6.89 (1H, dd, J=15.2, 9.9 Hz), 7.35 (1H, m), 7.48 (2H,d, J=8.6 Hz), 7.56 (2H, d, J=8.6 Hz), 7.78 (1H, s), 7.79 (1H, s).

EXAMPLE 38(RS)-2-(2,4-Difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-3-[[trans-2-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol

Reaction was carried out in the same manner as in Example 4 using(RS)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-3-methyl-1-(1H-1,2,4-triazol-1-yl)-2-butanoland (2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienal as describedin Reference example 25 to obtain the title compound, a major product asa colorless foam.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.36 (6H, s), 3.5-3.6 (2H, m),3.6-3.8 (2H, m), 4.2-4.4 (1H, m), 4.4-4.6 (1H, m), 4.93 (1H, d, J=14.1Hz), 5.03 (1H, d, J=4.3 Hz), 5.23 (1H, d, J=14.1 Hz), 5.56 (1H, s), 5.84(1H, dd, J=15.4, 4.3 Hz), 6.5-6.7 (3H, m), 6.7-6.9 (2H, m), 7.50 (2H, d,J=8.4 Hz), 7.57 (2H, d, J=8.4 Hz), 7.6-7.7 (1H, m), 7.74 (1H, s), 8.05(1H, s).

EXAMPLE 39(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[trans-2-[(E)-4-[4-(trifluoromethyl)phenyl]-1-buten-3-yn-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol

Reaction was carried out in the same manner as in Example 4 using(2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanoland (E)-5-[4-(trifluoromethyl)phenyl]-2-penten-4-ynal as described inReference example 48 to obtain the title compound, a major product as anoil in a yield of 70%.

Specific rotation [α]_(D) ²⁵ −65.1° (c=0.97, CHCl₃)

NMR spectrum (270 MHz, CDCl₃) δ ppm: 119 (3H, d, J=7.0 Hz), 3.33 (1H, q,J=7.0 Hz), 3.39 (1H, tt, J=11.4, 4.9 Hz), 3.60 (1H, t, J=11.4 Hz), 3.62(1H, t, J=11.4 Hz), 4.30 (1H, m), 4.42 (1H, m), 5.0-5.1 (2H, m), 5.04(1H, d, J=3.2 Hz), 6.12 (1H, d, J=16.0 Hz), 6.18 (1H, dd, J=16.0, 3.2Hz), 6.7-6.8 (2H, m), 7.36 (1H, m), 7.54 (2H, d, J=8.5 Hz), 7.58 (2H, d,J=8.5 Hz), 7.79 (2H, s).

EXAMPLE 40(2R,3R)-2-(2,4-Difluorophenyl)-3-[[trans-2-phenyl-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1yl)-2-butanol

In 20 ml of dimethylformamide were dissolved 1.65 g (6.57 mmol) of(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyl]oxiraneand 2.00 g (8.40 mmol) of trans-4-(acetylthio)-2-phenyl-1,3-dioxane asdescribed in Reference example 1, and 2.5 ml (4.00 mmol) of a 1.6 Msodium methoxide-methanol solution were added to the solution under anitrogen atmosphere, followed by heating of the resulting mixture withstirring at 65° C. for 2 hours. After cooling, ethyl acetate was addedto the reaction mixture and the resulting mixture was washed with asaturated aqueous NaCl solution and dried, followed by evaporation ofthe solvent under reduced pressure. The thus obtained crude product wassubjected to column chromatography using 60 g of silica gel and elutedwith a mixed solvent of benzene-ethyl acetate (5:1) to obtain 2.53 g(yield: 91%) of the title compound as a solid. The solid wasrecrystallized from ethyl acetate-hexane to obtain a pure product havinga melting point of 58 to 60° C.

Specific rotation [α]_(D) ²⁵ −88° (c=1.07, CHCl₃)

IR spectrum υ_(max) (CHCl₃)cm⁻¹: 3400, 1615, 1500, 1139.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.21 (3H, d, J=7.3 Hz), 3.36 (1H,q, J=7.3 Hz), 3.48 (1H, tt, J=11.2, 4.6 Hz), 3.75 (1H, t, J=11.2 Hz),3.77 (1H, t, J=11.2 Hz), 4.40 (1H, ddd, J=11.2, 4.6, 2.6 Hz), 4.51 (1H,ddd, J=11.2, 4.6, 2.6 Hz), 4.84 (1H, d, J=13.9 Hz), 5.02 (1H, s), 5.05(1H, d, J=13.9 Hz), 5.49 (1H, s), 7.7-7.8 (2H, m), 7.3-7.45 (4H, m),7.45-7.53 (2H, m), 7.79 (2H, s).

REFERENCE EXAMPLE 1 Trans-4-(acetylthio)-2-phenyl-1,3-dioxane

In 200 ml of dimethylformamide were dissolved 29.0 g (86.8 mmol) ofcis-2-phenyl-4-(p-toluenesulfonyloxy)-1,3-dioxane and 17.0 g (149 mmol)of sodium thioacetate, and the solution was heated at 115 to 120° C.under a nitrogen atmosphere for 1 hour. After cooling, benzene was addedto the reaction mixture and the mixture was washed with water, followedby evaporation of the solvent. The thus obtained brown residue wassubjected to column chromatography using silica gel and the fractionseluted with a mixed solvent of benzene-hexane (2:1) were collected,followed by recrystallization from a mixed solvent of benzene-hexane toobtain 8.99 g (yield: 43%) of the title compound having a melting pointof 95 to 96° C.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 2.37 (3H, s), 3.79 (2H, t, J=11.2Hz), 4 .03 (1H, tt, J=11.2, 4.6 Hz), 4.31 (2H, dd, J=11.2, 4.6 Hz), 5.47(1H, s), 7.35-7.5 (5H, m).

IR spectrum υ_(max) (CHCl₃) cm⁻¹: 1690, 1393, 1146, 1084.

Mass spectrum m/e: 238 (M⁺), 237, 195, 162(100%), 149, 116, 107, 73.

REFERENCE EXAMPLE 2(2R,3R)-2-(2,4-Difluorophenyl)-3-[(1,3-dihydroxy-2-propyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol

In 3.5 ml of methanol were dissolved 353 mg of(2R,3R)-2-(2,4-difluorophenyl)-3-[[trans-2-phenyl-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanolas described in Example 40, and 0.35 ml of a 4N HC1-dioxane solutionwere added to the solution, followed by stirring of the resultingmixture at room temperature for 30 minutes. To the reaction mixture wereadded 250 mg of a NaHCO₃ powder, and the mixture was stirred for 10minutes, followed by filtration of the reaction mixture andconcentration of the filtrate under reduced pressure. The thus obtainedoil was subjected to column chromatography using 5 g of silica gel andeluted with 10% methanol-ethyl acetate to obtain 179 mg (yield: 88%) ofthe title compound as a viscous oil.

Specific rotation [α]_(D) ²⁵ −61° (c=1.05, CHCl₃)

IR spectrum υ_(max)(CHCl₃)cm⁻¹: 3400, 1618, 1500.

NMR spectrum (60 MHz, CDCl₃+D₂O) δ ppm: 120 (3H, d, J=6.5 Hz), 3.0-4.0(6H, m), 4.80 (1H, d, J=14 Hz), 5.16 (1H, d, J=14 Hz), 6.6-7.0 (2H, m),7.43 (1H, td, J=9, 8 Hz), 7.74 (1H, s), 7.86 (1H, s).

REFERENCE EXAMPLE 3 Trans-5-[(4-chlorobenzyl)thio]-2-phenyl-1,3-dioxane

After 240 mg (5.50 mmol) of 55% sodium hydride were washed with hexane,it was suspended in 15 ml of dimethylformamide and 903 mg (5.70 mmol) of4-chlorobenzylmercaptane were added to the resulting suspension withstirring under nitrogen atmosphere. After 15 minutes, 1.66 g (4.96 mmol)of cis-5-(p-toluenesulfonyloxy)-2-phenyl-1,3-dioxane were added to themixture and the resulting mixture was stirred at 75° C. for 1 hour.After cooling, benzene was added to the reaction mixture and the mixturewas washed with water and then an aqueous NaCl solution. After thesolvent was distilled off, the thus obtained crystalline residue wasrecrystallized from a mixed solvent of benzene-hexane to obtain 670 mg(yield: 42%) of the title compound having a melting point of 95 to 99°C. as a flaky crystalline solid.

NMR spectrum (60 MHz, CDCl₃) δ ppm: 3.02 (1H, tt, J=11, 5 Hz), 3 (2H, t,J=11 Hz), 3.72 (2H, s), 4.21 (2H, dd, J=11, 5 Hz), 5.39 (1H, 7.30 (5H,s), 7.38 (4H, s).

REFERENCE EXAMPLE 4 2-[(4-Chlorobenzyl)thio]-1,3-propanediol

In 10 ml of methanol were dissolved 750 mg oftrans-5chlorobenzyl)thio]-2-phenyl-1,3-dioxane, and 1 ml of a 4Nhydrogen chloride-dioxane solution was added to the solution, followedby stirring of the resulting mixture at room temperature for 1 hour.After 750 mg of sodium hydrogencarbonate (powder) were added to thereaction mixture and the resulting mixture was stirred for 15 minutes,the solid was removed by filtration and the solvant was distilled off.Ethyl acetate was added to the residue and the insolubles were removedby filtration. The crystal obtained by evaporation of the solvent wasrecrystallized from a mixed solvent of benzene-hexane to obtain 468 mg(yield: 86%) of the title compound having a melting point of 70 to 75°C.

REFERENCE EXAMPLE 5 Trans-5-[(4-chlorobenzl)thio]-2-[(E)-1-methyl-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxane

In 12 ml of benzene were dissolved 341 mg (1.46 mmol) of2-[(4-chlorobenzyl)thio]-1,3-propanediol and 375 mg (1.75 mmol) of(E)-4-(trifluoromethyl)-α-methylcinnamaldehyde, and 3 mg ofp-toluenesulfonic acid were added to the solution, followed by heatingof the resulting mixture with reflux under nitrogen atmosphere for 2hours. After cooling, the reaction mixture was washed with an aqueoussodium hydrogencarbonate solution. The residue obtained by evaporationof the solvent was subjected to column chromatography using 15 g ofsilica gel. The fractions eluted with a mixed solvent of hexane-ethylacetate (9:1) were collected and the thus obtained solid was washed withhexane to obtain 370 mg (yield: 59%) of the title compound having amelting point of 93 to 95° C.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.87 (3H, s), 2.99 (1H, tt, J=11.2,4.6 Hz), 3.58 (2H, dd, J=11.9, 11.2 Hz), 3.73 (2H, s), 4.15 (2H, dd,J=11.9, 4.6 Hz), 4.87 (1H, s), 6.68 (1H, br s), 7.25-7.3 (4H, m), 7.36(2H, d, J=7.9 Hz), 7.57 (2H, d, J=7.9 Hz).

REFERENCE EXAMPLE 6Trans-5-[(4-chlorobenzyl)sulfinyl]-2-[(E)-1-methyl-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxane

In 10 ml of methylene chloride were dissolved 382 mg (0.89 mmol) oftrans-5-[(4-chlorobenzyl)thio]-2-[(E)-1-methyl-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxane,and 188 mg (0.92 mmol) of m-chloroperbenzoic acid (purity: 85%) wereadded to the solution, followed by stirring of the resulting mixture for15 minutes. The reaction mixture was washed with an aqueous sodiumhydrogencarbonate solution and the solid obtained by evaporation of thesolvent was washed with a mixed solvent of ethyl acetate-hexane toobtain 328 mg (yield: 83%) having a melting point of 192 to 194° C.

NMR spectrum (60 MHz, CDCl₃) δ ppm: 1.88 (3H, d, J=1.5 Hz), 2.8-3.3 (1H,m), 3.8-4.5 (4H, m), 4.01 (2H, s), 4.95 (1H, s), 6.73 (1H, br s),7.15-7.75 (8H, m).

REFERENCE EXAMPLE 7 Trans-4-(acetylthio)-2-[(E)-1-methyl-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxane

In 8 ml of a mixed solvent of tetrahydrofuran-acetonitrile (1:1) weredissolved 309 mg (0.696 mmol) oftrans-5-[(4-chlorobenzyl)sulfinyl]-2-[(E)-1-methyl-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxane, and 500 mg (4.67 mmol of2,6-lutidine were added to the solution. To the resulting mixture wereadded dropwise 500 mg (2.4 mmol) of trifluoroacetic anhydride withstirring at 0° C. for about 5 minutes. After 10 minutes, about 5 ml ofan aqueous sodium hydrogencarbonate solution were added to the reactionmixture and the mixture was stirred at 5 minutes, followed by extractionwith ethyl acetate. An oily residue (about 350 mg) obtained byevaporation of the solvent was dissolved in 5 ml of methylene chlorideand 210 mg of triethylamine were added to the solution at 0° C.,followed by addition of 109 mg of acetyl chloride to the resultingmixture. After 5 minutes, the reaction mixture was washed with water andthe solvent was distilled off. The residue was subjected to columnchromatography using 10 g of silica gel and eluted with a mixed solventof hexane-benzene (1:1 to 1:2) to obtain 186 mg (yield: 77%) of thetitle compound as a crystalline solid. The crystalline solid wasrecrystallized from a mixed solvent of benzene-hexane to obtain aplate-like crystalline solid having a melting point of 128 to 129° C.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.92 (3H, s), 2.36 (3H, s), 3.70(2H, t, J=11.2 Hz), 3.96 (1H, tt, J=11.2, 4.6 Hz), 4.25 (2H, dd, J=11.2,4.6 Hz), 4.94 (1H, s), 6.70 (1H, br s), 7.39 (2H, d,d J=8.2 Hz), 7.59(2H, d, J=8.2 Hz).

REFERENCE EXAMPLE 8 Ethyl(2E,4E)-3-methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienoate

After 45 mg (1.03 mmol) of 55% sodium hydride were washed with hexane,it was suspended in 3 ml of 1,2-dimethoxyethane and 273 mg (1.03 mmol)of triethyl 3-methyl-4-phosphonocrotonate were added to the resultingmixture with stirring at 0° C. under nitrogen atmosphere. After 15minutes, 100 mg (0.57 mmol) of 4-(trifluoromethyl)benzaldehyde wereadded to the mixture and the resulting mixture was stirred for 10minutes. After ice-water was added to the reaction mixture, the mixturewas extracted with ethyl acetate. The crude product obtained byevaporation of the solvent was subjected to column chromatography using5 g of silica gel and eluted with a mixed solvent of ethylacetate-hexane (4:96) to obtain 159 mg (yield: 97%) of a 5:1 mixture ofthe title compound, a (2E,4E) isomer and a (2Z,4E) isomer as an oil.

NMR spectrum (270 MHz, CDCl₃) δ ppm: (2E, 4E)-isomer, 1.31 (3H, t, J=6.6Hz), 2.41 (3H, s), 4.20 (2H, q, J=6.6 Hz), 5.95 (1H, s), 6.86 (1H, d,J=16.5 Hz), 6.95 (1H, d, J=16.5 Hz), 7.5-7.65 (4H, m): (2E, 4E)-isomer(main signal), 2.14 (3H, s), 5.82 (1H, s), 6.92 (1H, d, J=16.5 Hz), 8.49(1H, d, J=16.5 Hz).

REFERENCE EXAMPLE 9(2E,4E)-3-Methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadien-1-ol

After a solution in which 150 mg (0.53 mmol) of ethyl(4E)-3-methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienoate((2E)/(2Z)=5/1) as described in Reference example 8 were dissolved in 2ml of toluene was stirred at 0° C. 0.7 ml (1.06 mmol) of a 1.5Mdiisobutyl aluminum hybride-toluene solution were added to the solution.After 20 minutes, ice-water was added to the reaction mixture and themixture was stirred for 10 minutes. The insolubles were removed byfiltration using Celite and the filtrate was extracted with ethylacetate and dried, followed by evaporation of the solvent to obtain anoil. The oil was subjected to column chromatography using 5 g of silicagel and eluted with a mixed solvent of 30 to 40% ethyl acetate-hexane toobtain 90 mg of the title compound as an oil.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.34 (1H, br s), 1.93 (3H, s), 4.37(2H, d, J=6.5 Hz), 5.87 (1H, t, J=6.5 Hz), 6.58 (1H, d, J=16.1 Hz), 6.88(1H, J=16.1 Hz), 7.50 (2H, d, J=8.5 Hz), 7.57 (2H, d, J=8.5 Hz).

REFERENCE EXAMPLE 10(2E,4E)-3-Methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienal

In 10 ml of methylene chloride were dissolveed 460 mg (1.90 mmol) of(2E,4E)-3-methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadien-1-ol, and 5g of active manganese dioxide were added to the mixture, followed bystirring of the resulting mixture at room temperature of 30 minutes. Thesolid was removed by filtration, and after the filtrate wasconcentrated, it was purified over silica gel chromatography (elutingsolvent: 4% ethyl acetate-hexane) to obtain 460 mg of the title compoundas an oil.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 2.41 (3H, s), 6.13 (1H, d, J=8.0Hz), 6.96 (1H, d, J=16.1 Hz), 7.09 (1H, d, J=16.1 Hz), 7.55-7.7 (4H, m),10.19 (1H, d, J=8.0 Hz).

REFERENCE EXAMPLE 11 4-(Acetylthio)-1-(tert-butoxycarbonyl)piperidine

In 40 ml of dimethylformamide were dissolved 4.12 g (14.7 mmol) of1-(tert-butoxycarbonyl)-4-(methanesulfonyloxy)piperidine, and 2.53 g(2.21 mmol) of potassium thioacetate were added to the solution,followed by stirring of the resulting mixture at 105° C. for 4 hoursunder nitrogen atmosphere. After cooling, the reaction mixture wasdiluted with ethyl acetate and washed with water and then a saturatedaqueous NaCl solution, followed by evaporation of the solvent. The thusobtained residue was subjected to silica gel column chromatography andthe fractions eluted with a mixed solvent of hexane-ethyl acetate (5:1)were collected to obtain 5.19 g (yield: 81%) of the title compound as anoil.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.46 (9H, s), 1.5-1.6 (2H, m),1.9-2.0 (2H, m), 2.33 (3H, s), 3.0-3.1 (2H, m), 3.5-3.7 (1H, m), 3.8-3.9(2H, m).

Mass spectrum m/e: 259, 244, 216, 202, 186, 183, 160, 144, 127, 116, 97,84, 57.

REFERENCE EXAMPLE 12 1-(tert-Butoxycarbonyl)-4-mercaptopiperidine

In dry methanol were dissolved 520 mg (2 mmol) of4-(acetylthio)-1-(tert-butoxycarbonyl)piperidine, and 420 μl (2 mmol) ofa 28% sodium methoxide-methanol solution were added to the mixture underice-cooling and under a nitrogen atmosphere, followed by stirring of theresulting mixture for 40 minutes. Then, 173 μl of acetic acid were addedto the mixture and the solvent was distilled off at room temperature,followed by diluting of the residue with ethyl acetate. The mixture waswashed successively with an aqueous sodium hydrogencarbonate solutionand an aqueous NaCl solution in the order and the solvent was distilledoff to obtain 430 mg of reddish orange oil. This product was used for asubsequent reaction without purification.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.46 (9H, s), 1.5-1.6 (2H, m),1.9-2.0 (2H, m), 2.8-3.0 (3H, m), 3.9-4.1 (2H, m).

Mass spectrum m/e: 217, 202, 184, 161, 144, 127, 117, 84, 82.

REFERENCE EXAMPLE 13(2R,3R)-2-(2,4-Difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-3-[[1-(tert-butoxycarbonyl)piperidin-4-yl]thio]-2-butanol

In 6 ml of dimethylformamide was dissolved1-(tert-butoxycarbonyl)-4-mercaptopiperidine (corresponding to 2 mmol)as described in Reference example 12, and 86 mg (1.97 mmol) of 55%sodium hybride were added to the solution at 0° C. under a nitrogenatmosphere, followed by stirring of the resulting mixture at the sametemperature for 20 minutes. Then, 503 mg (2.00 mmol) of(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxiranewere added to the reaction mixture and the mixture was stirred at 60° C.for 3 hours. After cooling, ethyl acetate was added to the reactionmixture to dilute it and washed successively with water and a saturatedaqueous NaCl solution. An oil obtained by evaporation of the solvent wassubjected to silica gel column chromatography and eluted with ethylacetate to obtain 557 mg (yield: 53%) of the desired compound as an oil.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.17 (3H, d, J=6.6 Hz), 1.47 (9H,s), 1.4-1.6 (2H, m), 1.9-2.1 (2H, m), 2.9-3.1 (3H, m), 3.34 (1H, q,J=6.6 Hz), 3.9-4.1 (2H, m), 4.77 (1H, s), 4.82 (1H, d, J=14.2 Hz), 5.09(1H, d, J=14.2 Hz), 6.7-6.8 (2H, m), 7.3-7.4 (1H, m), 7.77 (1H, s), 7.82(1H, s).

IR spectrum υ_(max) ^(KBr)cm⁻¹: 3401, 1691.

Mass spectrum m/e: 468, 408, 395, 365, 321, 284, 253, 224, 188, 166,144, 127.

REFERENCE EXAMPLE 14 (2R,3R)-2-(2,4-Difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-3-[(piperidin-4-yl)thio]-2-butanol dihydrochloride

In 20 ml of ethyl acetate were dissolved 557 mg (1.05 mmol) of(2R,3R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-3-[[1-(tert-butoxycarbonyl)piperidin-4-yl]thiol]-2-butanol,and 2.63 ml (10.5 mmol) of a 4N hydrogen chloride-ethyl acetate solutionwere added to the solution, followed by stirring of the resultingmixture at 40° C. for 8 hours. After cooling, the precipitated solid wascollected by filtration and washed with hexane to obtain 460 mg (yield:100%) of the desired compound as a colorless powder.

NMR spectrum (270 MHz, DMSO-d6+CDCl₃) δ ppm: 1.23 (3H, d, J=6.6 Hz),1.8-2.0 (2H, m), 2.3-2.5 (2H, m), 3.1-3.4 (3H, m), 3.74 (1H, q, J=6.6Hz), 4.79 (1H, d, J=14.2 Hz), 5.05 (1H, d, J=14.2 Hz), 5.3-5.6 (1H, brs), 6.8-6.9 (1H, m), 7.0-7.1 (1H, m), 7.2-7.3 (1H, m), 7.79 (1H, s),8.28 (1H, s).

IR spectrum υ_(max) ^(KBr)cm⁻¹: 3366, 3094, 2725, 2483.

Mass spectrum m/e: 368, 308, 286, 284, 253, 224, 213, 183, 165, 144,116, 113, 84.

REFERENCE EXAMPLE 15 4-(Acetylthio)piperidine hydrochloride

In 45 ml of ethyl acetate were dissolved 1.25 g (4.82 mmol) of4-(acetylthio)-1-(tert-butoxycarbonyl)piperdine as described inReference example 11, and 12.0 ml (48.2 mmol) of a 4N hydrogenchloride-ethyl acetate solution were added to the solution, followed bystirring of the resulting mixture at 50° C. for 4 hours. After cooling,the precipitated solid was collected by filtration and washed withhexane to obtain 885 mg (yield: 94%) of the desired compound as aslightly yellow powder.

NMR spectrum (270 MHz, CD₃OD) δ ppm: 1.8-2.0 (2H, m), 2.1-2.3 (2H, m,2.35 (3H, s), 3.1-3.3 (2H, m), 3.3-3.5 (2H, m), 3.6-3.8 (1H, m).

REFERENCE EXAMPLE 164-(Acetylthio)-1-[(E)-4-(trifluoromethoxy)cinnamoyl]-piperidine

In 17 ml of dichloromethane were suspended 1.28 g (6.53 mmol) of4-(acetylthio)piperidine hydrochloride, and 2.27 ml (16.3 mmol) oftriethylamine were added dropwise to the suspension with stirring underice-cooling. Then, a solution in which 1.80 g (7.18 mmol) of(E)-4-(trifluoromethoxy)cinnamoyl chloride were dissolved in 6 ml ofdichloromethane was added dropwise to the reaction mixture, followed bystirring of the mixture at the same temperature for 1 hour. The reactionmixture was subjected to silica gel column chromatography and elutedwith a mixed solvent of hexane-ethyl acetate (2:1 to 1:1) to obtain 2.32g (yield: 95%) of the desired compound as a slightly yellow solid.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.5-1.7 (2H, m), 1.9-2.1 (2H, m),2.34 (3H, s), 3.1-3.3 (1H, m), 3.3-3.5 (1H, m), 3.7-3.8 (1H, m), 3.9-4.0(1H, m), 4.2-4.4 (1H, m), 6.85 (1H, d, J=15.5 Hz), 7.21 (2H, d, J=8.6Hz), 7.54 (2H, d, J=8.6 Hz), 7.63 (1H, d, J=15.5 Hz).

Mass spectrum m/e: 373, 330, 298, 256, 228, 215, 187, 158, 136, 116,101.

REFERENCE EXAMPLE 17 3-(Acetylthio)-1-(tert-butoxycarbonyl)azetidine

An orange oil obtained from1-(tert-butoxycarbonyl)-3-(methanesulfonyloxy) azetidine according tothe procedure of Reference example 11.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.44 (9H, s), 2.33 (3H, s), 3.81(2H, dd, J=9.0, 5.5 Hz), 4.1-4.2 (1H, m), 4.37 (2H, t, J=9.0 Hz).

REFERENCE EXAMPLE 18(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[1-(tert-butoxycarbonyl)azetidin-3-yl]thio]-2-butanol

A pale yellow foam obtained from3-(acetylthio)-1-(tert-butoxycarbonyl)azetidine according to theprocedure of Reference example 12 to 13.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.13 (3H, d, J=7.1 Hz), 1.45 (9H,s), 3.27 (1H, q, J=7.1 Hz), 3.7-3.9 (2H, m), 3.9-4.0 (1H, m), 4.2-4.4(2H, m), 4.84 (1H, d, J=14.1 Hz), 4.98 (1H, s), 5.04 (1H, d, J=14.1 Hz),6.7-6.9 (2H, m), 7.3-7.4 (1H, m), 7.78 (1H, s), 7.80 (1H, s).

IR spectrum υ_(max) ^(KBr)cm⁻¹: 3405, 1701.

Mass spectrum m/e: 441, 425, 385, 367, 341, 311, 284, 252, 224, 199,183, 165, 141, 127, 88.

REFERENCE EXAMPLE 19(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[(azetidin-3-yl)thio]-2-butanoldihydrochloride

A slightly yellow powder obtained from(2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[1-(tert-butoxycarbonyl)azetidin-3-yl]thio]-2-butanolaccording to the procedure of Reference example 14.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.16 (3H, d, J=6.6 Hz), 3.52 (1H,q, J=6.6 Hz), 3.9-4.3 (3H, m), 4.3-4.6 (2H, m), 4.98 (1H, d, J=14.2 Hz),5.43 (1H, d, J—14.2 Hz), 6.6-6.9 (2H, m), 7.2-7.4 (1H, m), 8.40 (1H, s),8.95 (1H, s), 9.0-9.6 (1H, br).

REFERENCE EXAMPLE 20 Ethyl trans-4-(trifluoromethyl)cinnamate

After 903 mg (20.7 mmol) of 55% sodium hydride were washed with hexane,it was suspended in 60 ml of 1,2-dimethoxyethane, and 4.63 g (20.7 mmol)of triethyl phosphonoacetate were added dropwise thereto while thesuspension was stirred at 0° C. under nitrogen atmosphere. After 15minutes, 2.00 g (11.5 mmol) of 4-(trifluoromethyl)benzaldehyde wereadded to the resulting mixture at the same temperature, followed bystirring of the mixture for 15 minutes. Ethyl acetate was added to thereaction mixture and the resulting mixture was washed with water. Afterdrying, an oily residue obtained by evaporation of the solvent wassubjected to column chromatography using silica gel and eluted with 4%ethyl acetate-hexane to obtain the title compound having a melting pointof 31 to 32.5° C. in a yield of 98%.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.35 (3H, t, J=7.3 Hz), 4.48 (2H,q, J=7.3 Hz), 6.51 (1H, d, J=16.2 Hz), 7.66 (4H, s), 7.69 (1H, d, J=16.2Hz).

REFERENCE EXAMPLE 21 Trans-4-(trifluoromethyl) cinnamyl alcohol

In 15 ml of toluene were dissolved 3.00 g (12.3 mmol) of ethyltrans-4-(trifluoromethyl)cinnamate, and 16.4 ml (24.6 mmol) of a 1.5Mdiisobutyl aluminum hydride-toluene solution were added to the solutionwith stirring at 0° C. After 20 minutes, ice-water was added to thereaction mixture and the mixture was stirred for 10 minutes, followed byremoval of the insolubles by filtration using Celite. The filtrate wasextracted with ethyl acetate and, after drying, the solvent wasdistilled off to obtain a crystalline residue. The residue wasrecrystallized from a mixed solvent of benzene-hexane to obtain 2.36 g(yield: 96%) of the title compound having a melting point of 53 to 55°C.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.55 (1H, t, J=5.9 Hz), 4.37 (2H,br t), 6.46 (1H, dt, J=16.2, 5.3 Hz), 6.67 (1H, d, J=16.2 Hz), 7.46 (2H,d, J=8.3 Hz), 7.57 (2H, d, J=8.3 Hz).

REFERENCE EXAMPLE 22 Trans-4-(trifluoromethyl) cinnamaldehyde

In 30 ml of methylene chloride were dissolved 2.15 g oftrans-4-(trifluoromethyl) cinnamyl alcohol, and 14 g of active manganesedioxide were added to the solution at 0° C., followed by stirring of theresulting mixture for 15 minutes and then stirring at room temperaturefor 2 hours. The solid was removed by filtration and the filtrate wasconcentrated to obtain a crystalline residue. The residue wasrecrystallized from a mixed solvent of benzene-hexane to obtain thetitle compound having a melting point of 60 to 61° C. in a yield of 90%.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 6.78 (1H, dd, J=16.2, 7.3 Hz), 7.53(1H, d, J=16.2 Hz), 7.69 (4H, s), 9.76 (1H, d, J=7.3 Hz).

IR spectrum υ_(max) (KBr) cm⁻¹: 1680, 1630, 1321, 1173, 1123, 1066.

Mass spectrum m/e: 200 (M⁺), 199, 171, 151, 145, 131 (100%), 103, 102.

REFERENCE EXAMPLE 23 Ethyl(2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienoate

After 4.51 g (103 mmol) of 55% sodium hydride were washed with hexane,it was suspended in 70 ml of 1,2-dimethoxyethane, and 25.9 g (103 mmol)of triethyl phosphonocrotonate were added dropwise thereto while thesuspension was stirred at 0° C. under nitrogen atmosphere. After 15minutes, 10.0 g (57.4 mmol) of 4-(trifluoromethyl)benzaldehyde was addedto the resulting mixture at the same temperature and the mixture wasstirred for 10 minutes. The reaction mixture was poured in ice-water,followed by extraction with ethyl acetate. The oily residue obtained byevaporation of the solvent was subjected to column chromatography usingsilica gel and eluted with 6% ethyl acetate-hexane to obtain 11.2 g(yield: 72%) of the title compound as an oil.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.32 (3H, t, J=7.3 Hz), 4.24 (2H,q, 7.3 Hz), 6.05 (1H, d, J=15.2 Hz), 6.85-7.0 (2H, m), 7.44 (1H, ddd,J=15.2, 7.9, 2.6 Hz), 7.55 (2H, d, J=8.6 Hz), 7.61 (2H, d, J=8.6 Hz).

REFERENCE EXAMPLE 24(2E,4E)-5-[4-(Trifluoromethyl)phenyl]-2,4-pentadien-1-ol

Ethyl (2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienoate wastreated with diisobutyl aluminum hybride in the same manner as inReference example 21 to obtain the title compound in quantitative yield.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.47 (1H, t, J=5.9 Hz), 4.28 (2H,t, J=5.9 Hz), 6.04 (1H, dt, J=15.2, 5.9 Hz), 6.45 (1H, dd, J=15.2, 10.6Hz), 6.57 (1H, d, J=15.8 Hz), 6.87 (1H, dd, J=15.8, 10.6 Hz), 7.47 (2H,d, J=8.6 Hz), 7.56 (2H, d, J=8.6 Hz).

REFERENCE EXAMPLE 25(2E,4E)-5-[4-(Trifluoromethyl)phenyl]-2,4-pentadienal

(2E,4E)-5-[4-(Trifluoromethyl)phenyl]-2,4-pentadien-1-ol was treatedwith active manganese dioxide in the same manner as in Reference example22 to obtain the title compound in a yield of 92%.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 6.33 (1H, dd, J=15.2, 7.3 Hz),7.0-7.35 (3H, m), 7.60 (2H, d, J=8.6 Hz), 7.64 (2H, d, J=8.6 Hz), 9.65(1H, d, J=7.3 Hz).

REFERENCE EXAMPLE 26 Ethyl(2E,4E,6E)-7-[4-(trifluoromethyl)phenyl]-2,4,6-heptatrienoate

(2E,4E)-5-[4-(Trifluoromethyl)phenyl]-2,4-pentadienal was reacted withtriethyl phosphonoacetate in the same manner as in Reference example 20to obtain the title compound in a yield of 95%.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.31 (3H, t, J=7.3 Hz), 4.23 (2H,q, J=7.3 Hz), 5.96 (1H, d, J=15.2 Hz), 6.49 (1H, dd, J=15.2, 11.2 Hz),6.72 (1H, dd, J=15.2, 10.6 Hz), 6.73 (1H, d, J=15.8 Hz), 6.94 (1H, dd,J=15.8, 10.6 Hz), 7.37 (1H, dd, J=15.2, 11.2 Hz), 7.51 (2H, d, J=8.6Hz), 7.58 (2H, d, J=8.6 Hz).

REFERENCE EXAMPLE 27

(2E,4E,6E)-7-[4-(Trifluoromethyl)phenyl]-2,4,6-heptatrien-1-ol

Ethyl (2E,4E,6E)-7-[4-(trifluoromethyl)phenyl]-2,4,6-heptatrienoate wastreated with diisobutyl aluminum hydride in the same manner as inReference example 21 to obtain the title compound in a yield of 90%.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.41 (1H, t, J=5.3 Hz), 4.25 (2H,t, J=5.3 Hz), 5.95 (1H, dt, J=15.0, 5.3 Hz), 6.3-6.5 (3H, m), 6.57 (1H,d, J=15.2 Hz), 6.90 (1H, m), 7.47 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.6Hz).

REFERENCE EXAMPLE 28

(2E,4E,6E)-7-[4-(Trifluoromethyl)phenyl]-2,4,6-heptatrienal

(2E,4E,6E)-7-[4-(Trifluoromethyl)phenyl]-2,4,6-heptatrien-1-ol wastreated with active manganese dioxide in the same manner as in Referenceexample 22 to obtain the title compound in a yield of 88%.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 6.23 (1H, dd, J=15.2, 7.9 Hz), 6.62(1H, dd, J=14.5, 11.2 Hz), 6.82 (1H, d, J=15.8 Hz), 6.84 (1H, dd,J=14.5, 9.9 Hz), 6.98 (1H, dd, J=15.8, 9.9 Hz), 7.19 (1H, dd, J=15.2,11.2 Hz), 7.54 (2H, d, J=8.6 Hz), 7.61 (2H, d, J=8.6 Hz), 9.62 (1H, d,J=7.9 Hz).

REFERENCE EXAMPLE 29

4-(2,2,3,3-Tetrafluoropropoxy)benzaldehyde

After 1.90 g (43.5 mmol) of 55% sodium hydride were washed with hexane,it was suspended in 25 ml of N,N-dimethylacetamide and 5.3 g (43 mmol)of 4-hydroxybenzaldehyde were gradually added to the suspension at 0° C.under nitrogen atmosphere. When generation of hydrogen gas stopped, 11.4g (39 mmol) of 2,2,3,3-tetrafluoropropyl p-toluenesulfonate were addedto the reaction mixture, followed by heating of the resulting mixture at120° C. with stirring for 2 hours and 15 minutes. After the reactionmixture was cooled, a mixed solvent of benzene-hexane (1:1) was addedthereto and the resulting mixture was washed with water. After drying,the solvent was distilled off to obtain 8.85 g (yield: 96%) of the titlecompound as an oil.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 4.45 (2H, br t, J=11.9 Hz), 6.06(1H, tt, J=53.3, 4.6 Hz), 7.06 (2H, d, J=8.7 Hz), 7.88 (2H, d, J=8.7Hz), 9.93 (1H, s).

REFERENCE EXAMPLE 30

Ethyl (2E,4E)-5-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-pentadienoate

4-(2,2,3,3-Tetrafluoropropoxy)benzaldehyde and triethylphosphonocrotonate were reacted in the same manner as in Referenceexample 23 to obtain the title compound having a melting point of 65 to66° C. in a yield of 74%.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.31 (3H, t, J=7.3 Hz), 4.23 (2H,q, J=7.3 Hz), 4.37 (2H, br t, J=11.9 Hz), 5.95 (1H, d, J=15.2 Hz), 6.06(1H, tt, J=53.5, 4.6 Hz), 6.77 (1H, dd, J=15.2, 9.9 Hz), 6.86 (1H, d,J=15.2 Hz), 6.91 (2H, d, J=8.6 Hz), 7.42 (1H, dd, J=15.2, 9.9 Hz), 7.44(2H, d, J=8.6 Hz).

REFERENCE EXAMPLE 31

(2E,4E)-5-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-2,4-pentadien-1-ol

Ethyl (2E,4E)-5-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-pentadienoatewas treated with diisobutyl aluminum hydride in the same manner as inReference example 21 to obtain the title compound having a melting pointof 95 to 97° C. in a yield of 95%.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.39 (1H, t, J=˜5 Hz), 4.25 (2H, t,J=5.9 Hz), 4.34 (2H, br t, J=11.9 Hz), 5.94 (1H, dt, J=15.1, 5.9 Hz),6.06 (1H, tt, J=53.2, 4.8 Hz), 6.40 (1H, dd, J=15.1, 10.3 Hz), 6.50 (1H,d, J=15.5 Hz), 6.69 (1H, dd, J=15.5, 10.3 Hz), 6.88 (2H, d, J=8.7 Hz),7.36 (2H, d, J=8.7 Hz).

REFERENCE EXAMPLE 32

(2E,4E)-5-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-2,4-pentadienal

Ethyl(2E,4E)-5-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-pentadien-1-ol wastreated with active manganese dioxide in the same manner as in Referenceexample 22 to obtain the title compound having a melting point of 53 to55° C. in a yield of 96%.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 4.38 (2H, br t, J=11.9 Hz), 6.06(1H, tt, J=52.8, 4.6 Hz), 6.25 (1H, dd, J=15.2, 7.9 Hz), 6.90 (1H, dd,J=15.8, 9.2 Hz), 6.94 (2H, d, J=8.6 Hz), 6.97 (1H, d, J=15.8 Hz), 7.25(1H, dd, J=15.2, 9.2 Hz), 7.48 (2H, d, J=8.6 Hz), 9.61 (1H, d, J=7.9Hz).

REFERENCE EXAMPLE 33

Trans-4-(trifluoromethoxy)cinnamaldehyde

570 mg (3.0 mmol) of 4-(trifluoromethoxy)benzaldehyde and 913 mg (3.0mmol) of (triphenylphosphoranylidene)acetaldehyde were heated underreflux in 7.5 ml of toluene under nitrogen atmosphere for 1 hour and 45minutes. The toluene was distilled off under reduced pressure and thethus obtained residue was purified over column chromatography using 20 gof silica gel. The fractions eluted with a mixed solvent of aceticacid-hexane (1:10) were collected to obtain 387 mg (yield: 60%) of thetitle compound as an oil.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 6.70 (1H, dd, J=15.8, 7.3 Hz), 7.29(2H, d, J=8.6 Hz), 7.47 (1H, d, J=15.8 Hz), 7.61 (2H, d, J=8.6 Hz), 9.72(1H, d, J=7.3 Hz).

IR spectrum ν_(max) (CHCl₃) cm⁻¹: 1680, 1508, 1259.

Mass spectrum m/e: 216 (M⁺), 215, 187, 175, 162, 131(100%), 119, 101.

REFERENCE EXAMPLE 34

Ethyl 6-(2,2,3,3,-tetrafluoropropoxy)nicotinate

After 840 mg (19.3 mmol) of 55% sodium hydride were washed with hexane,it was suspended in 40 ml of dimethylformamide, and 3.00 g (22.7 mmol)of 2,2,3,3-tetrafluoropropanol were gradually added to the suspension at0° C. under a nitrogen atmosphere. When generation of hydrogen gasstopped a solution in which 3.40 g (18.3 mmol) of ethyl6-chloronicotinate was dissolved in 15 ml of dimethylformamide was addeddropwise to the resulting mixture at the same temperature for about 30minutes. After the dropwise addition, the mixture was stirred for 30minutes and the reaction mixture was poured into ice-water, followed byextraction with benzene. After the extract was dried, the solvent wasdistilled off and the thus obtained oil was purified over columnchromatography [eluted with a mixed solvent of benzene-hexane (1:1)]using silica gel to obtain 4.42 g (yield: 86%) of the title compound asan oil.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.40 (3H, t, J=7.2 Hz), 4.39 (2H,q, J=7.2 Hz), 4.81 (2H, br t, J=12.6 Hz), 6.00 (1H, tt, J=53.0, 4.6 Hz),6.87 (1H, d, J=8.6 Hz), 8.24 (1H, dd, J=8.6, 2.5 Hz), 8.83 (1H, d, J=2.5Hz).

IR spectrum ν_(max) (CHCl₃) cm⁻¹: 1717, 1604, 1280, 1119.

Mass spectrum m/e: 281 (M⁺), 236(100%), 180, 152, 151, 123, 122, 93.

REFERENCE EXAMPLE 35

2-(2,2,3,3-Tetrafluoropropoxy)-5-(hydroxymethyl)pyridine

Ethyl 6-(2,2,3,3-tetrafluoropropoxy)nicotinate was reduced withdiisobutyl aluminum hydride in the same manner as in Reference example21 to obtain the title compound as an oil in a yield of 100%.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.69 (1H, t, J=5.8 Hz), 4.66 (2H,d, J=5.8 Hz), 4.74 (2H, br t, J=12.8 Hz), 6.01 (1H, tt, J=53.1, 4.6 Hz),6.84 (1H, d, J=8.5 Hz), 7.69 (1H, dd, J=8.5, 2.5 Hz), 8.12 (1H, d, J=2.5Hz).

Mass spectrum m/e: 239 (M⁺), 210, 188, 168, 138(100%), 109, 108, 78.

REFERENCE EXAMPLE 36

6-(2,2,3,3-Tetrafluoropropoxy)nicotinaldehyde

2-(2,2,3,3-Tetrafluoropropoxy)-5-(hydroxymethyl)pyridine was treatedwith active manganese dioxide in the same manner as in Reference example22 to obtain the title compound as an oil in a yield of 96%.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 4.86 (2H, br t, J=12.8 Hz), 6.01(1H, tt, J=53.3, 4.4 Hz), 6.97 (1H, d, J=8.6 Hz), 8.15 (1H, dd, J=8.6,2.3 Hz), 8.65 (1H, d, J=2.3 Hz).

Mass spectrum m/e: 237 (M⁺), 186, 166, 136(100%), 107, 106, 78.

REFERENCE EXAMPLE 37

(2E,4E)-5-[6-(2,2,3,3-Tetrafluoropropoxy)-3-pyridyl]-2,4-pentadienal

Following Reference examples 23, 24 and 25, the title compound having amelting point of 88 to 89° C. was obtained from6-(2,2,3,3-tyetrafluoropropoxy)nicotinaldehyde in 3 steps.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 4.78 (2H, br t, J=12.6 Hz), 6.01(1H, tt, J=53.3, 4.5 Hz), 6.28 (1H, dd, J=15.2, 7.9 Hz), 6.87 (1H, d,J=8.7 Hz), 6.85-7.0 (2H, m), 7.25 (1H, ddd, J=15.2, 7.8, 2.5 Hz), 7.85(1H, dd, J=8.7, 2.5 Hz), 8.23 (1H, d, J=2.5 Hz), 9.63 (1H, d, J=7.9 Hz).

IR spectrum ν_(max) (CHCl₃) cm⁻¹: 1677, 1626, 1591, 1488, 1290, 1120.

Mass spectrum m/e: 289 (M⁺), 260, 188, 178, 160, 145, 128, 117, 81,69(100%).

REFERENCE EXAMPLE 38

(2E,4E)-5-(6-Chloro-3-pyridyl)-2,4-pentadienal

Following Reference examples 23, 24 and 25, the title compound wasobtained as an oil from 6-chloronicotinaldehyde in 3 steps.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 6.32 (1H, dd, J=15.2, 7.8 Hz), 6.96(1H, d, J=15.4 Hz), 7.05 (1H, dd, J=15.4, 9.8 Hz), 7.26 (1H, dd, J=15.2,9.8 Hz), 7.36 (1H, d, J=8.3 Hz), 7.80 (1H, dd, J=8.3, 2.5 Hz), 8.48 (1H,d, J=2.5 Hz), 9.66 (1H, d, J=7.8 Hz).

REFERENCE EXAMPLE 39

[4-[(4-Chlorobenzyl)thio]cyclohexylidene]methyl methyl ether

After 146 mg (3.34 mmol) of 55% sodium hydride were washed with hexane,it was suspended in 18 ml of dimethyl sulfoxide, followed by stirring ofthe resulting suspension at 55° C. for 2 hours. The mixture was cooledto room temperature and 1.26 g (3.34 mmol) ofmethoxymethyltriphenylphosphonium chloride were added to the mixture.Further, a solution in which 426 mg (1.67 mmol) of4-[(4-chlorobenzyl)thio]cyclohexanone were dissolved in 5 ml of dimethylsulfoxide was added to the resulting mixture. Water was added to themixture and the resulting mixture was extracted with toluene. After theextract was dried, the crude product obtained by evaporation of thesolvent was subjected to column chromatography using 20 g of silica geland eluted with a mixed solvent of methylene chloridehexane (1:4) toobtain 370 mg (yield: 78%) of the title compound as an oil.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.2-1.5 (2H, m), 1.7-2.0 (3H, m),2.0-2.2 (1H, m), 2.5-2.8 (2H, m), 3.53 (3H, s), 3.71 (2H, s), 5.77 (1H,s), 7.27 (4H, s).

IR spectrum ν_(max) (CHCl₃) cm⁻¹: 2935, 1689, 1491, 1443, 1123.

Mass spectrum m/e: 282, 157, 124, 109.

REFERENCE EXAMPLE 40

Trans-4-[(4-chlorobenzyl)thio]cyclohexanecarboxaldehyde

In 20 ml of acetone were dissolved 955 mg (3.4 mmol) of[4-[(4-chlorobenzyl) thio]cyclohexylidene]methyl methyl ether, and 5 mlof water were added to the solution, followed by addition of 1 ml of 5Nhydrochloric acid. The mixture was stirred at 55° C. for 20 minutes. Themixture was concentrated under reduced pressure and the residue wasextracted with ethyl acetate. After the extract was dried, the crudeproduct obtained by evaporation of the solvent was subjected to columnchromatography using 15 g of silica gel and eluted with a mixed solventof methylene chloride-hexane (1:3) to obtain 865 mg (yield: 95%) of a1:1 mixture of a trans isomer, the title compound, and a cis isomer asan oil.

This product was stirred in 15 ml of a 0.07N sodium methoxidemethanolsolution at room temperature for 2 to 3 hours. To the mixture was added0.2 ml of acetic acid, and the resulting mixture was diluted with ethylacetate and washed with an aqueous NaCl solution. After the mixture wasdried, the solvent was distilled off to obtain 865 mg of a 4:1 mixtureof the title trans form and a cis form as a solid. The solid wasrecrystallized from a mixed solvent of etherhexane to obtain 220 mg ofthe trans form title compound having a melting point of 44 to 46° C.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.2-1.5 (4H, m), 1.9-2.15 (2H, m),2.15-2.35 (1H, m), 2.35-2.55 (1H, m), 3.73 (2H, s), 7.27 (5H, s), 9.61(1H, s).

Cis isomer exhibited a signal at δ 3.67 (2H, s) and δ 9.64 (1H, s).

IR spectrum ν_(max) (CHCl₃) cm⁻¹: 2927, 1732, 1493, 1448, 1092.

Mass spectrum m/e: 268, 240, 127, 125, 110.

REFERENCE EXAMPLE 41

4-Chlorobenzyltrans-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadienyl]cyclohexylsulfide

After 50 mg (1.14 mmol) of 55% sodium hydride were washed with hexane,it was suspended in 7 ml of dimethyl sulfoxide, followed by stirring ofthe suspension at 55° C. for 2.5 hours. The mixture was cooled to roomtemperature and 607 mg (1.26 mmol) of [(E)-4-(trifluoromethyl)cinnamyl]triphenylphosphonium chloride were added thereto. Further, 170mg (0.63 mmol) of trans-4-[(4-chlorobenzyl)thio]cyclohexanecarboxaldehyde were added to the resulting mixture,followed by stirring of the mixture at room temperature for 15 minutes.The mixture was diluted with toluene and washed with water and anaqueous NaCl solution. After the mixture was dried, the crude productobtained by evaporation of the solvent was subjected to columnchromatography using 5 g of silica gel and eluted with a mixed solventof methylene chloride-hexane (1:2). The eluted portion wasrecrystallized from hexane to obtain 86 mg (yield: 31%) of the titlecompound having a melting point of 142 to 144° C.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.1-1.3 (2H, m), 1.3-1.5 (2H, m),1.7-2.0 (2H, m), 2.0-2.2 (2H, m), 2.64 (1H, tt, J=12.4 Hz), 3.74 (2H,s), 5.81 (1H, dd, J=15, 7 Hz), 6.20 (1H, dd, J=15, 10 Hz), 6.47 (1H, d,J=16 Hz), 6.81 (1H, dd, J=16, 10 Hz), 7.29 (4H, s), 7.46 (2H, d, J=8Hz), 7.55 (2H, d, J=8 Hz).

IR spectrum ν_(max) (KBr) cm⁻¹: 1641, 1612, 1490, 1326, 1167, 1127,1069.

Mass spectrum m/e: 436, 417, 403, 311, 277, 235, 159, 125.

REFERENCE EXAMPLE 42

4-chlorobenzyltrans-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadienyl]cyclohexylsulfoxide

In 20 ml of methylene chloride were dissolved 211 mg (0.48 mmol) of4-chlorobenzyltrans-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadienyl]cyclohexylsulfide, and 104 mg (0.48 mmol) of m-chloroperbenzoic acid (purity: 80%)were added to the solution at 0° C. followed by stirring of theresulting mixture for 5 minutes. An aqueous sodium sulfite solution andethyl acetate were added to the reaction mixture and the organic layerwas washed with an aqueous sodium hydrogencarbonate solution and anaqueous NaCl solution. After the mixture was dried, the crude productobtained by evaporation of the solvent was recrystallized from a mixedsolvent of ethyl acetate-hexane to obtain 168 mg (yield: 77%) of thetitle compound having a melting point of 212 to 214° C.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.1-1.3 (2H, m), 1.5-1.8 (2H, m),1.9-2.3 (5H, m), 2.42 (1H, tt, J=12, 4 Hz), 3.87 (1H, d, J=13 Hz), 3.97(1H, d, J=13 Hz), 5.80 (1H, dd, J=15, 7 Hz), 6.22 (1H, dd, J=15, 10 Hz),6.48 (1H, d, J=16 Hz), 6.80 (1H, dd, J=16, 10 Hz), 7.25 (2H, d, J=8 Hz),7.36 (2H, d, J=8 Hz), 7.45 (2H, d, J=8 Hz), 7.55 (2H, d, J=8 Hz).

IR spectrum ν_(max) (KBr) cm⁻¹: 1612, 1492, 1325, 1168, 1128, 1069.

Mass spectrum m/e: 452, 436, 327, 278, 277, 159, 125.

REFERENCE EXAMPLE 43

Trans-1-(acetyltio)-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]cyclohexane

In 11 ml of a mixed solvent of tetrahydrofuran-acetonitrile (8:3) weredissolved 178 mg (0.39 mmol) of 4-chlorobenzyltrans-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadienyl]cyclohexyl sulfoxide, and 168 mg (1.57 mmol) of2,6-lutidine were added to the solution. To the mixture were added 165mg (0.79 mmol) of trifluoroacetic anhydride with stirring at 0° C. After3 minutes, an aqueous sodium hydrogencarbonate solution was added to themixture, followed by extraction with ethyl acetate. The oily residueobtained by evaporation of the solvent was dissolved in 10 ml ofmethylene chloride, and 119 mg (1.17 mmol) of triethylamine were addedto the mixture at 0° C., followed by addition of 62 mg (0.79 mmol) ofacetyl chloride to the resulting mixture. After 1 hour, the reactionmixture was diluted with ethyl acetate and washed with an aqueous sodiumhydrogencarbonate solution and an aqueous NaCl solution. After themixture was dried, the crude product obtained by evaporation of thesolvent was subjected to column chromatography using 5 g of silica geland eluted with a mixed solvent of methylene chloride-hexane (1:1),followed by purification over Rover column [GrosseB, a mixed solvent ofethyl acetate-hexane (1:19)] to obtain 98 mg (yield: 70%) of the titlecompound having a melting point of 113 to 115° C.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.2-1.5 (4H, m), 1.7-1.9 (2H, m),2.0-2.2 (3H, m), 2.31 (3H, s), 3.37 (1H, tt, J=12, 4 Hz), 5.82 (1H, dd,J=15, 7 Hz), 6.20 (1H, dd, J=15, 10 Hz), 6.47 (1H, d, J=16 Hz), 6.81(1H, dd, J=16, 10 Hz), 7.45 (2H, d, J=8 Hz), 7.54 (2H, d, J=8 Hz).

IR spectrum ν_(max) (KBr) cm⁻¹: 1688, 1613, 1326, 1157, 1117, 1068.

Mass spectrum m/e: 354, 335, 311, 277, 235, 159.

REFERENCE EXAMPLE 44

3-[4-(Trifluoromethyl)phenyl]-2-propyn-1-ol

In 50 ml of diethylamine were dissolved 5.0 g (22 mmol) of4-bromo-α,α,α-trifluorotoluene and 1.25 g (22 mmol) of propargylalcohol, and 80 mg (0.11 mmol) of bis(triphenylphosphine)palladium (II)chloride and 40 mg (0.22 mmol) of copper (I) iodide were added to thesolution, followed by stirring of the resulting mixture at 50° C. for 35minutes. To the mixture were added 40 mg (0.06 mmol) ofbis(triphenylphosphine)palladium (II) chloride, and the resultingmixture was stirred for a further 35 minutes. After the mixture wasdried, the crude product obtained by evaporation of the solvent wassubjected to column chromatography using 50 g of silica gel and elutedwith a mixed solvent of ethyl acetate-hexane (3:17) to obtain 2.21 g(yield: 50%) of the title compound as an oil.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.8 (1H, br, OH), 4.52 (2H, s),7.54 (2H, d, J=9 Hz), 7.57 (2H, d, J=9 Hz).

IR spectrum ν_(max) (CHCl₃) cm⁻¹: 3610, 1618, 1324, 1172, 1133, 1069,1019, 844.

Mass spectrum m/e: 200, 183, 171, 151, 131.

REFERENCE EXAMPLE 45

3-[4-(Trifluoromethyl)phenyl]-2-propynal

In 20 ml of methylene chloride were dissolved 2.21 g (11.0 mmol) of3-[4-(trifluoromethyl)phenyl]-2-propyn-1-ol, and 7.43 g (17.5 mmol) ofDess-Martin reagent were added to the solution under ice-cooling for 1.7hours. Benzene was added to the resulting mixture and the insolubleswere removed by filtration, followed by concentration of the filtrate toobtain 1.83 g (yield: 84%) of the title compound as an oil.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 7.68 (2H, d, J=9 Hz), 7.71 (2H, d,J=9 Hz), 9.45 (1H, s).

IR spectrum ν_(max) (CHCl₃) cm⁻¹: 2197, 1664, 1324, 1175, 1138.

Mass spectrum m/e: 198, 197, 170, 151, 120.

REFERENCE EXAMPLE 46

Ethyl (E)-5-[(4-trifluoromethyl)phenyl]-2-penten-4-ynoate

After 181 mg (4.54 mmol) of 55% sodium hydride were washed with hexane,it was suspended in 10 ml of 1,2-dimethoxyethane, and 1.02 g (4.54 mmol)of triethyl 4-phosphonoacetate were added to the suspension withstirring at 0° C. under nitrogen atmosphere. After 20 minutes, 500 mg(2.52 mmol) of 3-[4-(trifluoromethyl)phenyl]-2-propynal were added tothe mixture, followed by stirring of the resulting mixture for 20minutes. The reaction mixture was diluted with ethyl acetate, ice wasadded to the mixture and then the organic layer was washed with water.The crude product obtained by distilling off the solvent was subjectedto column chromatography using 15 g of silica gel and eluted withbenzene to obtain 488 mg (yield: 72%) of the title compound as an oil.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.32 (3H, t, J=7 Hz), 4.25 (2H, q,J=7 Hz), 6.35 (1H, d, J=16 Hz), 6.97 (1H, d, J=16 Hz), 7.5-7.7 (4H, m).

IR spectrum ν_(max) (CHCl₃) cm⁻¹: 1712, 1622, 1316, 1174, 1134.

Mass spectrum m/e: 268, 240, 223, 195, 183, 175.

REFERENCE EXAMPLE 47

(E)-5-[4-(Trifluoromethyl)phenyl]-2-penten-4-yn-1-ol

In 4 ml of toluene were dissolved 480 mg (1.79 mmol) of ethyl(E)-5-[4-(trifluoromethyl)phenyl]-2-penten-4-ynoate, and 2.38 ml (3.58mmol) of a 1.5 M diisobutyl aluminum hydride-toluene solution were addedto the solution with stirring at 0° C. After 10 minutes, ice was addedto the mixture and the insolubles were removed by filtration usingCelite. After the organic layer was dried, the crude product obtained byevaporation of the solvent was subjected to column chromatography using15 g of silica gel and eluted with a mixed solvent of ethylacetate-hexane (3:17) to obtain 353 mg (yield: 87%) of the titlecompound as an oil.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.60 (1H, br OH), 4.31 (2H, br),5.99 (1H, d, J=16 Hz), 6.40 (1H, dt, J=16, 5 Hz), 7.54 (2H, d, J=9 Hz),7.57 (2H, d, J=9 Hz).

REFERENCE EXAMPLE 48

(E)-5-[4-(Trifluoromethyl)phenyl]-2-penten-4-ynal

In 4 ml of methylene chloride were dissolved 350 mg (1.56 mmol) of(E)-5-[4-(trifluoromethyl)phenyl]-2-penten-4-yn-1-ol, and 3.5 g ofactive manganese dioxide were added to the solution, followed bystirring of the resulting mixture at room temperature for 30 minutes.The solid was removed by filtration and the filtrate was concentrated.Then, the filtrate was subjected to column chromatography using 10 g ofsilica gel and eluted with a mixed solvent of ethyl acetate-hexane(1:214) to obtain 245 mg (yield: 70%) of the title compound as an oil.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 6.58 (1H, dd, J=16, 8 Hz), 6.82(1H, d, J=16 Hz), 7.63 (4H, s), 9.65 (1H, d, J=8 Hz).

IR spectrum νmax (CHCl₃) cm⁻¹: 1670, 1325, 1132, 1119, 1107, 1072, 845.

Mass spectrum m/e: 224, 196, 195, 175, 170, 146.

REFERENCE EXAMPLE 49

Methyl (Z)-4-chloro-β-(trifluoromethyl)cinnamate

In 10 ml of tetrahydrofuran were dissolved 150 g (0.47 mmol) ofbis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate, and 0.94ml (0.47 mmol) of a 0.5M potassium hexamethyldisilazide-toluene solutionwere added dropwise to the mixture with stirring at −78° C. undernitrogen atmosphere. Then, 622 mg (2.36 mmol) of 18-crown-6 were addedto the mixture and the resulting mixture was stirred for 20 minutes,followed by addition of a solution in which 98 mg (0.47 mmol) of4′-chloro-2,2,2-trifluoroacetophenone were dissolved in 1 ml oftetrahydrofuran. The temperature of the reaction mixture was slowlyelevated to room temperature and a saturated aqueous ammonium chloridesolution was added to the mixture, followed by extraction with ethylacetate. The crude product obtained by evaporation of the solvent waspurified over column chromatography (eluted with 4% ethylacetate-hexane) using silica gel to obtain 89 mg (yield: 70%, containingabout {fraction (1/10)} of (E)-isomer) of the title compound as an oil.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 3.85 (3H, s), 6.34 (1H, s), 7.34(2H, d, J=8.6 Hz), 7.39 (2H, d, J=8.6 Hz).

REFERENCE 50 (Z)-4-Chloro-β-(trifluoromethyl)cinnamaldehyde

Following Reference examples 21 and 22, the title compound was obtainedas an oil in a yield of 81% from methyl (z)-4-chloro-δ-(trifluoromethyl)cinnamate in 2 steps.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 6.36 (1H, d, J=7.3 Hz), 7.38 (2H,d, J=8.6 Hz), 7.44 (2H, d, J=8.6 Hz), 10.21 (1H, dq, J=7.3, 2.0 Hz).

REFERENCE EXAMPLE 51 Methyl(2E,4Z)-5-(4-chlorophenyl)-6,6,6-trifluoro-2,4-hexadienoate

(Z)-4- Chloro-β-(trifluoromethyl)cinnamaldehyde and trimethylphosphonocrotonate were reacted in the same manner as in Referenceexample 23 to obtain the title compound as an oil in a yield of about90% (separation and purification by column chromatography).

NMR spectrum (270 MHz, CDCl₃) δ ppm: 3.81 (3H, s), 6.15 (1H, d, J=15.2Hz), 6.59 (1H, d, J=11.9 Hz), 7.31 (2H, d, J=8.6 Hz), 7.38 (1H, d, J=8.6Hz), 7.48 (1H, ddq, J=15.2, 11.9, 2.0 Hz).

REFERENCE EXAMPLE 52(2E,4Z)-5-(4-Chlorophenyl)-6,6,6-trifluoro-2,4-hexadienal

Following Reference examples 21 and 22, the title compound was obtainedas an oil in a yield of 71% from methyl(2E,4Z)-5-(4-chlorophenyl)-6,6,6-trifluoro-2,4-hexadienoate in 2steps.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 6.37 (1H, dd, J=15.2, 7.3 Hz), 6.72(1H, d, J=11.9 Hz), 7.33 (2H, d, J=8.6 Hz), 7.40 (2H, d, J=8.6 Hz), 7.64(1H, ddq, J=15.2, 11.9, 2 Hz), 9.74 (1H, d, J=7.3 Hz).

REFERENCE EXAMPLE 53 2-Methyl-2-[(trans-2-phenyl-1,3-dioxan-5-yl)thio]-4′-(trifluoromethyl)propiophenone

In 3.8 ml of dimethylformamide were dissolved 619 mg (2.10 mmol) of2-bromo-2-methyl-4′-(trifluoromethyl)propiophenone and 500 mg (2.1 mmol)of trans-4-acethylthio-2-phenyl-1,3-dioxane, and 0.44 ml (2.10 mmol) ofa 28% sodium methoxide-methanol solution were added to the solution withstirring at room temperature under nitrogen atmosphere. After 30minutes, water was added to the reaction mixture and the resultingmixture was extracted with ethyl acetate. The solvent was evaporated toobtain 860 mg (yield: ˜100%) of the title compound as a solid.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.61 (6H, s), 4.42 (1H, tt, J=11.6,5.0 Hz), 3.64 (2H, t, J=11.6 Hz), 4.12 (2H, dd, J=11.6, 5.0 Hz), 5.38(1H, s) 7.3-7.5 (5H, m), 7.68 (2H, d, J=8.2 Hz), 8.19 (2H, d, j=8.2 Hz).

REFERENCE EXAMPLE 54(RS)-3-Methyl-3-[(trans-2-phenyl1,3-dioxan-55-yl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol

680 mg (1.66 mmol) of2-methyl-2-[(trans-2-phenyl-1,3-dioxan-5-yl)thio]-4′-(trifluoromethyl)propiophenone,547 mg (2.49 mmol) of trimethylsulfoxonium iodide, 381 mg (6.79 mmol) ofpotassium hydroxide and 264 mg (3.82 mmol) of 1,2,4-triazole were heatedwith stirring in 5.7 ml of t-butanol at 80° C. for 6 hours. Aftercooling, the reaction mixture was distributed between chloroform andwater and the chloroform layer was separated and dried, followed byevaporation of the solvent. The thus obtained oil was subjected tocolumn chromatography using silica gel and eluted with a mixed solventof ethyl acetate-hexane (1:1) to obtain 605 mg (yield: 74%) of the titlecompound as a foam.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.38 (3H, s), 1.39 (3H, s),3.55-3.8 (3H, m), 4.33 (1H, m), 4.54 (1H, m), 5.02 (2H, s), 5.37 (1H,s), 5.44 (1H, s), 7.3-7.6 (5H, m), 7.73 (1H, s), 7.94 (1H, s).

REFERENCE EXAMPLE 55(RS)-3-[(1,3-Dihydroxy-2-propyl)thio]-3-methyl-2-[4-(trifluoromethyl)phenyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol

(RS)-3-Methyl-3-[(trans-2-phenyl-1,3-dioxan-5-yl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol was treatedwith HC1 in methanol in the same manner as in Reference example 2 toobtain the title compound as a foam.

NMR spectrum (270 MHz, CDCl₃) δ ppm: 1.30 (3H, s), 1.42 (3H, s), 3.35(1H, m), 3.55-3.8 (3H, m), 3.96 (1H, dd, J=10.9, 5.4 Hz), 4.83 (3H, s),5.26 (1H, d, J=14.6 Hz), 5.34 (1H, d, J=14.6 Hz), 7.53 (2H, d, J=8.3Hz), 7.70 (1H, s), 7.75 (2H, d, J=8.3 Hz), 8.26 (1H, s).

REFERENCE EXAMPLE 56 2-(p-Toluenesulfonyloxy)-1,3-propanediol

In 50 ml of methanol were dissolved 5.00 g ofcis-2-phenyl-4-(p-toluenesulfonyloxy)-1,3-dioxane, and 5 ml of a 4NHC1-dioxane solution were added to the solution, followed by stirring ofthe resulting mixture at room temperature for 2 hours. To the reactionmixture were added 3.5 g of NaHCO₃ powder, and the mixture was stirredfor 10 minutes. Then, the reaction mixture was filtered and the filtratewas concentrated under reduced pressure. The thus obtained oil wassubjected to column chromatography using silica gel and eluted withethyl acetate to obtain 3.70 g (yield: 100%) of the title compound as anoil.

NMR spectrum (60 MHz, CDCl₃) δ ppm: 2.40 (3H, s), 3.30 (2H, s), 3.73(4H, d, J=4.55 Hz), 4.5 (1H, quintet, J=4.5 Hz), 7.33 (2H, d, J=8 Hz),7.84 (2H, d, J=8 Hz).

REFERENCE EXAMPLE 57Cis-4-(p-toluenesulfonyloxy)-2-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxane-

In 4.5 ml of methylene chloride were dissolved 200 mg (0.81 mmol) of2-(p-toluenesulfonyloxy)-1,3-propanediol and 206 mg (0.91 mmol) of(2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienal, and 15 mg ofp-toluenesulfonic acid and 0.8 g of molecular sieves 4A were added tothe solution, followed by stirring of the resulting mixture of 0° C. for1hour. An aqueous sodium hydrogencarbonate solution was added to thereaction mixture and the mixture was stirred for 10 minutes. Then, themolecular sieves were removed by filtration and the filtrate wasextracted with methylene chloride. The oil obtained by evaporation ofthe solvent was separated by preparative thin layer chromatography ofsilica gel (developing solvent: 20% ethyl acetate-hexane) to obtain 107mg (yield: 29%) of a trans isomer having less polarity and 153 mg(yield: 42%) of a cis isomer having higher polarity as an oil,respectively.

NMR spectrum (270 MHz, CDCl₃) of cis isomer δ ppm: 2.45 (3H, s), 3.99(2H, br d, J=13.2 Hz), 4.19 (2H, br d, J=13.2 Hz), 4.45 (1H, br s), 5.09(1H, d, J=4.6 Hz), 5.82 (1H, dd, J=15.2, 4.6 Hz), 6.57 (1H, dd, J=15.2,10.5 Hz), 6.63 (1H, d, J=15.2 Hz), 6.82 (1H, dd, J=15.2, 10.5 Hz), 7.36(2H, d, J=8.6 Hz), 7.48 (2H, d, J=8.6 Hz), 7.56 (2H, d, J=8.6 Hz), 7.85(2H, d, J=8.6 Hz).

Test Example 1

To mice (one group consisting of 10 mice), which were innoculated with 4to 9=10⁶ Candida albicans, were administered orally 20 mg/kg ofpreparations after 1, 4 and 24 hours, and thereafter the survival rateuntil 21 days after infection was examined. The results of comparisonthe compound (I) of the present invention with commercially availableFluconazol are shown in Table 2. From the results, it is apparent thatthe compound (I) exhibits an excellent antifungal activity.

TABLE 2 Survival rate % Compound 14 days 21 days Example  2 100 100 11100 100 15 100 100 16 100 100 18 100 100 21 100  60 30 100 100 32 100100 35 100 100 37 100 100 Fluconazol  70  60

Preparation Example 1

Capsule

Compound of Examples 1 to 39 or 40 50 mg Lactose 128 mg  Corn starch 70mg Magnesium stearate  2 mg 250 mg 

The thus formulated powder was mixed and passed through a sieve of 60mesh, and then the powder was encapsulated in No. 3gelatin capsule of250 mg to prepare a capsule.

Preparation Example 2

Tablet

Compound of Examples 1 to 39 or 40 50 mg Lactose 126 mg  Corn starch 23mg Magnesium stearate  1 mg 200 mg 

The thus formulated powder was mixed and wet-granulated using a cornstarch sizing agent and dried, and then a 200 mg-tablet was made bymeans of a tablet making machine. If necessary, sugar coating can beapplied to the tablet.

The compound having the general formula (I) or a pharmacologicallyacceptable salt thereof of the present invention has an excellentantifungal activity and is useful as an antifungal agent.

What is claimed is:
 1. A triazole compound having the formula:

wherein Ar¹ represents an unsubstituted phenyl group or a phenyl grouphaving 1 to 3 substituents selected form the group consisting of ahalogen atom and a trifluoromethyl group; Ar₂ represents anunsubstituted phenyl group or a phenyl group having 1 to 3 substituentsselected from the group consisting of an unsubstituted lower alkylgroup, an unsubstituted lower alkoxy group, a halogen atom, a halosubstituted lower alkyl group, a halo substituted lower alkoxy group, anitro group, a cyano group, a -S(0 )_(m)R⁶ group, wherein R⁶ representsan unsubstituted lower alkyl group or a halo substituted lower alkylgroup and m represents 0, 1 or 2, or a -NHCOR⁷ group, wherein R⁷represents a lower alkyl group; R⁰ represents a hydrogen atom or a loweralkyl group; R¹ represents a lower alkyl group; R², R³, R⁴ and R⁵ arethe same or different and each is a hydrogen atom, an unsubstitutedlower alkyl group or a halo substituted lower alkyl group and, where qand/or s represent 2, each of R², R³, R⁴ and R⁵ represents independentlya group which is the same or different from the other R², R³, R⁴ and R⁵respectively; n represents 0, 1 or 2; p represents 0 or 1; q, r and seach represent 0, 1 or 2; and A represents a 4- to 7-membered aliphaticheterocyclic group having one nitrogen atom, or a pharmacologicallyacceptable salt thereof.
 2. The triazole compound or a pharmacologicallyacceptable salt thereof according to claim 1, wherein Ar¹ is a phenylgroup having 1 to 3 substituents selected from the group consisting of ahalogen atom and a trifluoromethyl group.
 3. The triazole compound or apharmacologically acceptable salt thereof according to claim 1, whereinAr¹ is a phenyl group having 1 or 2 substituents selected from the groupconsisting of a fluorine atom, a chlorine atom and a trifluoromethylgroup.
 4. The triazole compound or a pharmacologically acceptable saltthereof according to claims 1 2, or 3, wherein Ar² represents anunsubstituted phenyl group.
 5. The triazole compound or apharmacologically acceptable salt thereof according to claims 1 2, or 3,wherein Ar² represents a phenyl group having 1 to 3 substituentsselected from the group consisting of an unsubstituted lower alkylgroup, a halogen atom, a halo substituted lower alkyl group a halosubstituted lower alkoxy group, a nitro group, a cyano group or a—S(O)_(m)R⁶ group, wherein R⁶ represents an unsubstituted or halosubstituted lower alkyl group and m represents 0, 1 or
 2. 6. Thetriazole compound or a pharmacologically acceptable salt thereofaccording to claims 1 2, or 3, wherein Ar² represents a phenyl grouphaving 1 or 2 substituents selected from the group consisting of anunsubstituted lower alkyl group, a halogen atom, a halo substitutedlower alkyl group, a halo substituted lower alkoxy group, a nitro group,a cyano group or a -S(O)_(m)R⁶ group, wherein R⁶ represents anunsubstituted or halo substituted lower alkyl group and m represents 0,1 or
 2. 7. The triazole compound or a pharmacologically acceptable saltthereof according to claims 1, 2 or 3, wherein R⁰ is a hydrogen atom, amethyl group, an ethyl group or a propyl group.
 8. The triazole compoundor a pharmacologically acceptable salt thereof according to claims 1, 2or 3, wherein R⁰ is a hydrogen atom, a methyl group or an ethyl group.9. The triazole compound or a pharmacologically acceptable salt thereofaccording to claims 1, 2 or 3, wherein R⁰ is a hydrogen atom or a methylgroup.
 10. The triazole compound or a pharmacologically acceptable saltthereof according to claims 1, 2 or 3, wherein R¹ is a methyl group, anethyl group or a propyl group.
 11. The triazole compound or apharmacologically acceptable salt thereof according to claims 1, 2 or 3,wherein R¹ is a methyl group or an ethyl group.
 12. The triazolecompound or a pharmacologically acceptable salt thereof according toclaims 1, 2 or 3, wherein R¹ is a methyl group.
 13. The triazolecompound or a pharmacologically acceptable salt thereof according toclaims 1, 2 or 3, wherein R², R³, R⁴ and R⁵ are the same or differentand are a hydrogen atom, an unsubstituted lower alkyl group or afluorine or chlorine substituted lower alkyl group.
 14. The triazolecompound or a pharmacologically acceptable salt thereof according toclaims 1, 2 or 3, wherein R², R³, R⁴ and R⁵ are the same or differentand are a hydrogen atom, an unsubstituted methyl group, an unsubstitutedethyl group, an unsubstituted propyl group, a fluorine or chlorinesubstituted methyl group, a fluorine or chlorine substituted ethyl groupor a fluorine or chlorine substituted propyl group.
 15. The triazolecompound or a pharmacologically acceptable salt thereof according toclaims 1, 2 or 3, wherein R², R³, R⁴ and R⁵ are the same or differentand are a hydrogen atom, an unsubstituted methyl group, an unsubstitutedethyl group, a fluorine or chlorine substituted methyl group or afluorine or chlorine substituted ethyl group.
 16. The triazole compoundor a pharmacologically acceptable salt thereof according to claims 1, 2or 3, wherein R², R³, R⁴ and R⁵ are the same or different and are ahydrogen atom or an unsubstituted methyl group or a fluorine or chlorinesubstituted methyl group.
 17. The triazole compound or apharmacologically acceptable salt thereof according to claims 2 or 3,wherein n is 0 or
 1. 18. The triazole compound or a pharmacologicallyacceptable salt thereof according to claims 1, 2 or 3, wherein n is 0.19. The triazole compound or a pharmacologically acceptable salt thereofaccording to claims 2 or 3, wherein p is
 0. 20. The triazole compound ora pharmacologically acceptable salt thereof according to claims 2 or 3,wherein q, r and s are each 0 or
 1. 21. The triazole compound or apharmacologically acceptable salt thereof according to claims 1, 2, or3, wherein A is a 4- to 6-membered aliphatic heterocyclic group havingone nitrogen atom.
 22. The triazole compound or a pharmacologicallyacceptable salt thereof according to claims 1, 2 or 3, wherein A is apiperidine group.
 23. An antifungal composition comprising an antifungaleffective amount of the triazole compound or a pharmacologicallyacceptable salt thereof according to claims 1, 2 of 3 as an activeingredient in combination with a pharmacological acceptable carrier ordiluent.
 24. The triazole compound or a pharmacologically acceptablesalt thereof according to claim 1, wherein R⁰ is a hydrogen atom, amethyl group, an ethyl group or a propyl group; R¹ is a methyl group, anethyl group or a propyl group; and R², R³, R⁴ and R⁵ are independentlyselected from the group consisting of a hydrogen atom, an unsubstitutedmethyl group, an unsubstituted ethyl group, an unsubstituted propylgroup, a methyl group substituted by fluorine, a methyl groupsubstituted by a chlorine, an ethyl group substituted by fluorine, anethyl group substituted by a chlorine, a propyl group substituted byfluorine and a propyl group substituted by a chlorine; A is a piperidinegroup or an azetidine group; and Ar² is unsubstituted phenyl,4-chlorophenyl, 4-(trifluoromethylthio)phenyl,4-(trifluoromethylsulfonyl)phenyl, 4-(trifluoromethyl)phenyl,4-trifluoromethoxy)phenyl or 4-(2,2,3,3-tetrafluoropropoxy)phenyl.
 25. Amethod of treating a patient suffering from a Candida albicans mycoticdisease comprising administering to the patient an effectiveanti-fungicidal amount of the triazole compound of claim 1 or apharmacologically acceptable salt thereof.
 26. The triazole compound ora pharmacologically acceptable salt thereof according to claim 1,wherein the compound is(2R,3R)-2-(2,4-difluorophenyl)-3-[[1-[(E)-4-(trifluoromethoxy)cinnamoyl]piperidin-4-yl]-1-1(1H-1,2,4-triazol-1yl)-2-butanol.27. The triazole compound or pharmacologically acceptable salt thereofaccording to claim 1, wherein the compound is(2R,3R)-2-(2,4-difluorophenyl)-3-[[1-((E)-4-methylcinnamoyl)piperidin-4-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol.
 28. Thetriazole compound or pharmacologically acceptable salt thereof accordingto claim 1, wherein the compound is(2R,3R)-2-(2,4-difluorophenyl)-3-[[1-((E)-4-nitroeinnamoyl)piperidin-4-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol.29. The triazole compound or pharmacologically acceptable salt thereofaccording to claim 1, wherein the compound is(2R,3R)-2-(2,4,difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[1-[(2E,4E)-5-[4-(trifluoromethoxy)phenyl]-2,4-pentadienoyl]piperidin-4-yl]thio]-2-butanol.30. The triazole compound or pharmacologically acceptable salt thereofaccording to claim 1, wherein the compound is (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-((E)-4- (trifluoromethoxy)cinnamoyl]azetidin-3-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol. 31.The antifungal composition according to claim 23, wherein the triazolecompound is selected from the group consisting of(2R,3R)-2-(2,4-difluorophenyl)-3-[[1-((E)-4-(trifluoromethoxy)cinnamoyl]piperidin-4-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol,(2R,3R)-2-(2,4-difluorophenyl)-3-[[-((E)-4-methylcinnamoyl)piperidin-4-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol,(2R,3R)-2-(2,4-difluorophenyl)-3-[[1-((E)-4-nitrocinnamoyl)piperidin-4-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol,(2R,3R)-2-(2,4,difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[[1-[(2E,4E)-5-[4-(trifluoromethoxy)phenyl]-2,4-pentadienoyl]piperidin-4-yl]thio]-2-butanol,(2R,3R)-2-(2,4-difluorophenyl)-3-[[1-((E)-4-(trifluoromethoxy)cinnamoyl]azetidin-3-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanoland pharmacologically acceptable salts thereof.
 32. The method accordingto claim 25, wherein the triazole compound is selected from the groupconsisting of(2R,3R)-2-(2,4-difluorophenyl)-3-[[1-((E)-4-(trifluoromethoxy)cinnamoyl]piperidin-4yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol,(2R,3R)-2-(2,4-difluorophenyl)-3-[[1-((E)-4-methylcinnamoyl)piperidin-4-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol,(2R,3R)-2-(2,4-difluorophenyl)-3-[[1-((E)-4-nitrocinnamoyl)piperidin-4-yl]thio]-1-(1H-1,2,4-triazol-1yl)-2-butanol,(2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1yl)-3-[[1-[(2E,4E)-5-[4-trifluoromethoxy)phenyl]-2,4-pentadienoyl[piperidin-4yl]thio]-2-butanol,(2R,3R)-2-(2,4-difluorophenyl)-3-[[1-((E)-4-(trifluoromethoxy)cinnamoyl]azetidin-3-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol andpharmacologically acceptable salts thereof.
 33. The triazole compound ora pharmacologically acceptable salt thereof according to claim 1,wherein A is an azetidine group.